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  • 1.
    Alizadeh, Javad
    et al.
    University of Manitoba, Canada.
    Zeki, Amir A.
    Centre Comparat Resp Biol and Med, CA USA.
    Mirzaei, Nima
    University of Manitoba, Canada.
    Tewary, Sandipan
    University of Manitoba, Canada.
    Rezaei Moghadam, Adel
    University of Manitoba, Canada; University of Manitoba, Canada.
    Glogowska, Aleksandra
    University of Manitoba, Canada.
    Nagakannan, Pandian
    University of Manitoba, Canada.
    Eftekharpour, Eftekhar
    University of Manitoba, Canada.
    Wiechec, Emilia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Logopedi, Audiologi och Otorhinolaryngologi. Linköpings universitet, Medicinska fakulteten.
    Gordon, Joseph W.
    University of Manitoba, Canada; University of Manitoba, Canada; University of Manitoba, Canada.
    Xu, Fred. Y.
    University of Manitoba, Canada; University of Manitoba, Canada.
    Field, Jared T.
    University of Manitoba, Canada.
    Yoneda, Ken Y.
    Centre Comparat Resp Biol and Med, CA USA.
    Kenyon, Nicholas J.
    Centre Comparat Resp Biol and Med, CA USA.
    Hashemi, Mohammad
    Zehedan University of Medical Science, Iran.
    Hatch, Grant M.
    University of Manitoba, Canada; University of Manitoba, Canada.
    Hombach-Klonisch, Sabine
    University of Manitoba, Canada.
    Klonisch, Thomas
    University of Manitoba, Canada.
    Ghavami, Saeid
    University of Manitoba, Canada; University of Manitoba, Canada; Shiraz University of Medical Science, Iran.
    Mevalonate Cascade Inhibition by Simvastatin Induces the Intrinsic Apoptosis Pathway via Depletion of Isoprenoids in Tumor Cells2017Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, artikkel-id 44841Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The mevalonate (MEV) cascade is responsible for cholesterol biosynthesis and the formation of the intermediate metabolites geranylgeranylpyrophosphate (GGPP) and farnesylpyrophosphate (FPP) used in the prenylation of proteins. Here we show that the MEV cascade inhibitor simvastatin induced significant cell death in a wide range of human tumor cell lines, including glioblastoma, astrocytoma, neuroblastoma, lung adenocarcinoma, and breast cancer. Simvastatin induced apoptotic cell death via the intrinsic apoptotic pathway. In all cancer cell types tested, simvastatin-induced cell death was not rescued by cholesterol, but was dependent on GGPP-and FPP-depletion. We confirmed that simvastatin caused the translocation of the small Rho GTPases RhoA, Cdc42, and Rac1/2/3 from cell membranes to the cytosol in U251 (glioblastoma), A549 (lung adenocarcinoma) and MDA-MB231( breast cancer). Simvastatin-induced Rho-GTP loading significantly increased in U251 cells which were reversed with MEV, FPP, GGPP. In contrast, simvastatin did not change Rho-GTP loading in A549 and MDA-MB-231. Inhibition of geranylgeranyltransferase I by GGTi-298, but not farnesyltransferase by FTi-277, induced significant cell death in U251, A549, and MDA-MB-231. These results indicate that MEV cascade inhibition by simvastatin induced the intrinsic apoptosis pathway via inhibition of Rho family prenylation and depletion of GGPP, in a variety of different human cancer cell lines.

  • 2.
    Banerjee, Debarshi
    et al.
    Columbia University Medical Center, USA.
    Cieslar-Pobuda, Artur
    University of Oslo, Norway.
    Zhu, Geyunjian Harry
    University of Cambridge, UK.
    Wiechec, Emilia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Patra, Hirak
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Department of Chemical Engineering and Biotechnology, University of Cambridge, UK; Wolfson College, University of Cambridge, UK.
    Adding nanotechnology to the metastasis treatment arsenal2019Inngår i: TIPS - Trends in Pharmacological Sciences, ISSN 0165-6147, E-ISSN 1873-3735, Vol. 40, nr 6, s. 403-418Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Metastasis is a major cause of cancer-related mortality, accounting for 90% of cancer deaths. The explosive growth of cancer biology research has revealed new mechanistic network information and pathways that promote metastasis. Consequently, a large number of antitumor agents have been developed and tested for their antimetastatic efficacy. Despite their exciting cytotoxic effects on tumor cells in vitro and antitumor activities in preclinical studies in vivo, only a few have shown potent antimetastatic activities in clinical trials. In this review, we provide a brief overview of current antimetastatic strategies that show clinical efficacy and review nanotechnology-based approaches that are currently being incorporated into these therapies to mitigate challenges associated with treating cancer metastasis.

    Fulltekst tilgjengelig fra 2020-05-07 12:06
  • 3.
    Bose, Tanima
    et al.
    Leibniz Inst Neurobiol, D-39 Magdeburg, Germany.
    Cieślar-Pobuda, Artur
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet. Silesian Tech Univ, Inst Automat Control, Biosyst Grp, PL-44100 Gliwice, Poland.
    Wiechec, Emilia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Role of ion channels in regulating Ca2+ homeostasis during the interplay between immune and cancer cells.2015Inngår i: Cell Death and Disease, ISSN 2041-4889, E-ISSN 2041-4889, Vol. 19, nr 6, artikkel-id e1648Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Ion channels are abundantly expressed in both excitable and non-excitable cells, thereby regulating the Ca2+ influx and downstream signaling pathways of physiological processes. The immune system is specialized in the process of cancer cell recognition and elimination, and is regulated by different ion channels. In comparison with the immune cells, ion channels behave differently in cancer cells by making the tumor cells more hyperpolarized and influence cancer cell proliferation and metastasis. Therefore, ion channels comprise an important therapeutic target in anti-cancer treatment. In this review, we discuss the implication of ion channels in regulation of Ca2+ homeostasis during the crosstalk between immune and cancer cell as well as their role in cancer progression.

  • 4.
    Cieslar-Pobuda, Artur
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Wiechec-Los, Emilia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Editorial Material: Research on liver regeneration as an answer to the shortage of donors for liver transplantation in HEPATOLOGY RESEARCH, vol 44, issue 9, pp 944-9462014Inngår i: Hepatology Research, ISSN 1386-6346, E-ISSN 1872-034X, Vol. 44, nr 9, s. 944-946Artikkel i tidsskrift (Annet vitenskapelig)
    Abstract [en]

    n/a

  • 5.
    Cieślar-Pobuda, Artur
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Institute of Automatic Control, Silesian University of Technology, Gliwice, Poland.
    Vilas Jain, Mayur
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Kratz, Gunnar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Hand- och plastikkirurgiska kliniken US.
    Rzeszowska-Wolny, Joanna
    Institute of Automatic Control, Silesian University of Technology, Gliwice, Poland.
    Ghavami, Saeid
    Department of Human Anatomy and Cell Science, University of Manitoba, Manitoba, Canada.
    Wiechec, Emilia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    The expression pattern of PFKFB3 enzyme distinguishes between induced-pluripotent stem cells and cancer stem cells.2015Inngår i: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 6, nr 30, s. 29753--29770Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Induced pluripotent stem cells (iPS) have become crucial in medicine and biology. Several studies indicate their phenotypic similarities with cancer stem cells (CSCs) and a propensity to form tumors. Thus it is desirable to identify a trait which differentiates iPS populations and CSCs. Searching for such a feature, in this work we compare the restriction (R) point-governed regulation of cell cycle progression in different cell types (iPS, cancer, CSC and normal cells) based on the expression profile of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase3 (PFKFB3) and phosphofructokinase (PFK1). Our study reveals that PFKFB3 and PFK1 expression allows discrimination between iPS and CSCs. Moreover, cancer and iPS cells, when cultured under hypoxic conditions, alter their expression level of PFKFB3 and PFK1 to resemble those in CSCs. We also observed cell type-related differences in response to inhibition of PFKFB3. This possibility to distinguish CSC from iPS cells or non-stem cancer cells by PFKB3 and PFK1 expression improves the outlook for clinical application of stem cell-based therapies and for more precise detection of CSCs.

  • 6.
    Farahani, Ensieh
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Patra, Hirak Kumar
    Linköpings universitet, Institutionen för fysik, kemi och biologi. Linköpings universitet, Tekniska högskolan.
    Jangamreddy, Jaganmohan Reddy
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Rashedi, Iran
    University of Toronto, ON, Canada.
    Kawalec, Martha
    University of Manitoba, Winnipeg, Canada .
    Rao Pariti, Rama K.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Batakis, Petros
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi. Linköpings universitet, Tekniska högskolan.
    Wiechec, Emilia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Cell adhesion molecules and their relation to (cancer) cell stemness2014Inngår i: Carcinogenesis, ISSN 0143-3334, E-ISSN 1460-2180, Vol. 35, nr 4, s. 747-759Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Despite decades of search for anticancer drugs targeting solid tumors, this group of diseases remains largely incurable, especially if in advanced, metastatic stage. In this review, we draw comparison between reprogramming and carcinogenesis, as well as between stem cells (SCs) and cancer stem cells (CSCs), focusing on changing garniture of adhesion molecules. Furthermore, we elaborate on the role of adhesion molecules in the regulation of (cancer) SCs division (symmetric or asymmetric), and in evolving interactions between CSCs and extracellular matrix. Among other aspects, we analyze the role and changes of expression of key adhesion molecules as cancer progresses and metastases develop. Here, the role of cadherins, integrins, as well as selected transcription factors like Twist and Snail is highlighted, not only in the regulation of epithelial-to-mesenchymal transition but also in the avoidance of anoikis. Finally, we briefly discuss recent developments and new strategies targeting CSCs, which focus on adhesion molecules or targeting tumor vasculature.

  • 7.
    Ghavami, S.
    et al.
    University of Manitoba, Winnipeg, Canada.
    Hashemi, M.
    Zahedan University of Medical Sciences, Iran .
    Ande, S. R.
    MICB, CancerCare Manitoba, Winnipeg, Canada.
    Yeganeh, B.
    St Boniface General Hospital Research Centre and University of Manitoba, Winnipeg, Canada.
    Xiao, W.
    MICB, CancerCare Manitoba, Winnipeg, Canada.
    Eshraghi, M.
    MICB, CancerCare Manitoba, Winnipeg, Canada.
    Bus, C. J.
    University of Tübingen, Germany.
    Kadkhoda, K.
    University of Manitoba and Diagnostic Services of Manitoba, Winnipeg, Canada .
    Wiechec, Emilia
    University of Aarhus, Denmark.
    Halayko, A. J.
    University of Manitoba, Winnipeg, Canada.
    Los, Marek
    University of Tübingen, Germany.
    Apoptosis and cancer: mutations within caspase genes2009Inngår i: Journal of Medical Genetics, ISSN 0022-2593, E-ISSN 1468-6244, Vol. 46, nr 8, s. 497-510Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    The inactivation of programmed cell death has profound effects not only on the development but also on the overall integrity of multicellular organisms. Beside developmental abnormalities, it may lead to tumorigenesis, autoimmunity, and other serious health problems. Deregulated apoptosis may also be the leading cause of cancer therapy chemoresistance. Caspase family of cysteinyl-proteases plays the key role in the initiation and execution of programmed cell death. This review gives an overview of the role of caspases, their natural modulators like IAPs, FLIPs, and Smac/Diablo in apoptosis and upon inactivation, and also in cancer development. Besides describing the basic mechanisms governing programmed cell death, a large part of this review is dedicated to previous studies that were focused on screening tumours for mutations within caspase genes as well as their regulators. The last part of this review discusses several emerging treatments that involve modulation of caspases and their regulators. Thus, we also highlight caspase cascade modulating experimental anticancer drugs like cFLIP-antagonist CDDO-Me; cIAP1 antagonists OSU-03012 and ME-BS; and XIAP small molecule antagonists 1396-11, 1396-12, 1396-28, triptolide, AEG35156, survivin/Hsp90 antagonist shephedrin, and some of the direct activators of procaspase-3.

  • 8.
    Gurevich-Panigrahi, Tatiana
    et al.
    BioApplication Enterprises, Winnipeg, Canada.
    Wiechec, Emilia
    Manitoba Institute of Cell Biology, CancerCare Manitoba; Department of Human Genetics, University of Aarhus, Aarhus, Denmark.
    Panigrahi, Soumya
    Department of Immunology, Lerner Research Institute, Cleveland, USA.
    Los, Marek Jan
    Interfaculty Institute for Biochemistry, University of Tübingen, Germany; BioApplications Enterprises, Winnipeg, MB, Canada.
    Obesity: Pathophysiology and Clinical2009Inngår i: Current Medicinal Chemistry, ISSN 0929-8673, E-ISSN 1875-533X, Vol. 16, nr 4, s. 506-521Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Obesity is an increasingly serious socioeconomic and clinical problem. Between 1/4 - 1/3 of population in the developed countries can be classified as obese. Four major etiological factors for development of obesity are genetic determinants, environmental factors, food intake and exercise. Obesity increases the risk of the development of various pathologic conditions including: insulin-resistant diabetes mellitus, cardiovascular disease, non-alcoholic fatty liver disease, endocrine problems, and certain forms of cancer. Thus, obesity is a negative determinant for longevity. In this review we provide broad overview of pathophysiology of obesity. We also discuss various available, and experimental therapeutic methods. We highlight functions of adipocytes including fat storing capacity and secretory activity resulting in numerous endocrine effects like leptin, IL-6, adiponectin, and resistin. The anti-obesity drugs are classified according to their primary action on energy balance. Major classes of these drugs are: appetite suppressants, inhibitors of fat absorption (i.e. orlistat), stimulators of thermogenesis and stimulators of fat mobilization. The appetite suppressants are further divided into noradrenergic agents, (i.e. phentermine, phendimetrazine, benzphetamine, diethylpropion), serotoninergic agents (i.e. dexfenfluramine), and mixed noradrenergic-serotoninergic agents (i.e. sibutramine). Thus, we highlight recent advances in the understanding of the central neural control of energy balance, current treatment strategies for obesity and the most promising targets for the development of novel anti-obesity drugs.

  • 9.
    Hashemi, Mohammad
    et al.
    Zahedan University of Medical Sciences, Iran.
    Karami, Shima
    Zahedan University of Medical Sciences, Iran.
    Sarabandi, Sahel
    Zahedan University of Medical Sciences, Iran.
    Moazeni-Roodi, Abdolkarim
    Iranshahr University of Medical Sciences, Iran.
    Malecki, Andrzej
    The Jerzy Kukuczka Academy of Physical Education, Katowice, Poland.
    Ghavami, Saeid
    University of Manitoba, Canada.
    Wiechec, Emilia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Association between PD-1 and PD-L1 polymorphisms and the risk of cancer: a meta analysis of case-control studies2019Inngår i: Cancers, ISSN 2072-6694, Vol. 11, nr 8, artikkel-id 1150Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A number of case-control studies regarding the association of the polymorphisms in the programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) genes with the risk of cancer have yielded inconsistent findings. Therefore, we have conducted a comprehensive, updated meta-analysis study to identify the impact of PD-1 and PD-L1 polymorphisms on overall cancer susceptibility. The findings revealed that PD-1 rs2227981 and rs11568821 polymorphisms significantly decreased the overall cancer risk (Odds Ratio (OR) = 0.82, 95% CI = 0.68–0.99, p = 0.04, TT vs. CT+CC; OR = 0.79, 95% CI = 0.67–0.94, p = 0.006, AG vs. GG, and OR = 0.82, 95% CI = 0.70–0.96, p = 0.020, AG+AA vs. GG, respectively), while PD-1 rs7421861 polymorphism significantly increased the risk of developing cancer (OR = 1.16, 95% CI = 1.02–1.33, p = 0.03, CT vs. TT). The PD-L1 rs4143815 variant significantly decreased the risk of cancer in homozygous (OR = 0.62, 95% CI = 0.41–0.94, p = 0.02), dominant (OR = 0.70, 95% CI = 0.50–0.97, p = 0.03), recessive (OR = 0.76, 95% CI = 0.60–0.96, p = 0.02), and allele (OR = 0.78, 95% CI = 0.63–0.96, p = 0.02) genetic models. No significant association between rs2227982, rs36084323, rs10204525, and rs2890658 polymorphisms and overall cancer risk has been found. In conclusions, the results of this meta-analysis have revealed an association between PD-1 rs2227981, rs11568821, rs7421861, as well as PD-L1 rs4143815 polymorphisms and overall cancer susceptibility. 

  • 10.
    Hombach-Klonisch, Sabine
    et al.
    Department Human Anatomy and Cell Science, University of Manitoba, Winnipeg, Canada .
    Paranjothy, Ted
    Manitoba Institute of Cell Biology, CancerCare Manitoba, Winnipeg, Canada .
    Wiechec, Emilia
    Department of Human Genetics, University of Aarhus, Aarhus, Denmark.
    Pocar, Paola
    Department of Animal Science, Faculty of Veterinary Medicine, University of Milan, Milan, Italy .
    Mustafa, Tarek
    Department of Oral and Maxillo-Facial Surgery, Faculty of Medicine, University Magdeburg, Magdeburg, Germany; Experimental Surgery and Oncology Research Group, Department of General, Visceral and Vascular Surgery, University of Halle-Wittenberg, Halle, Germany .
    Seifert, Anja
    Department Anatomy and Cell Biology, University of Halle-Wittenberg, Halle, Germany .
    Zahl, Christian
    Department of Oral and Maxillo-Facial Surgery, Faculty of Medicine, University Magdeburg, Magdeburg, Germany .
    Luis Gerlach, Klaus
    Department of Oral and Maxillo-Facial Surgery, Faculty of Medicine, University Magdeburg, Magdeburg, Germany .
    Biermann, Katharina
    Institute of Pathology, University Hospital Bonn, Bonn, Germany .
    Steger, Klaus
    Department of Urology and Pediatric Urology, University of Giessen, Giessen, Germany .
    Hoang-Vu, Cuong
    Experimental Surgery and Oncology Research Group, Department of General, Visceral and Vascular Surgery, University of Halle-Wittenberg, Halle, Germany .
    Schulze-Osthoff, Klaus
    Institute of Molecular Medicine, University of Düsseldorf, Düsseldorf, Germany .
    Los, Marek Jan
    Manitoba Institute of Cell Biology, CancerCare Manitoba, Winnipeg, Canada; BioApplications Enterprises, Winnipeg, MB, Canada.
    Cancer stem cells as targets for cancer therapy: selected cancers as examples2008Inngår i: Archivum Immunologiae et Therapiae Experimentalis, ISSN 0004-069X, E-ISSN 1661-4917, Vol. 56, nr 3, s. 165-180Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    It is becoming increasingly evident that cancer constitutes a group of diseases involving altered stem-cell maturation/differentiation and the disturbance of regenerative processes. The observed malignant transformation is merely a symptom of normal differentiation processes gone astray rather than the primary event. This review focuses on the role of cancer stem cells (CSCs) in three common but also relatively under-investigated cancers: head and neck, ovarian, and testicular cancer. For didactic purpose, the physiology of stem cells is first introduced using hematopoietic and mesenchymal stem cells as examples. This is followed by a discussion of the (possible) role of CSCs in head and neck, ovarian, and testicular cancer. Aside from basic information about the pathophysiology of these cancers, current research results focused on the discovery of molecular markers specific to these cancers are also discussed. The last part of the review is largely dedicated to signaling pathways active within various normal and CSC types (e.g. Nanog, Nestin, Notch1, Notch2, Oct3 and 4, Wnt). Different elements of these pathways are also discussed in the context of therapeutic opportunities for the development of targeted therapies aimed at CSCs. Finally, alternative targeted anticancer therapies arising from recently identified molecules with cancer-(semi-)selective capabilities (e.g. apoptin, Brevinin-2R) are considered.

  • 11.
    Iranpour, Mahmoud
    et al.
    National Microbiology Laboratory, Canada.
    Moghadam, Adel R.
    Islamic Azad University.
    Yazdi, Mina
    University of Tehran.
    Ande, Sudharsana R.
    University of Manitoba.
    Alizadeh, Javad
    University of Manitoba.
    Wiechec, Emilia
    Linköpings universitet, Medicinska fakulteten. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap.
    Lindsay, Robbin
    National Microbiology Laboratory, Canada.
    Drebot, Michael
    National Microbiology Laboratory, Canada.
    Coombs, Kevin M.
    University of Manitoba.
    Ghavami, Saeid
    University of Manitoba.
    Apoptosis, autophagy and unfolded proteinresponse pathways in Arbovirus replicationand pathogenesis2016Inngår i: Expert Reviews in Molecular Medicine, ISSN 1462-3994, E-ISSN 1462-3994, Vol. 18, nr e1, s. 21-Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Arboviruses are pathogens that widely affect the health of people in different communities around the world. Recently, a few successful approaches toward production of effective vaccines against some of these pathogens have been developed, but treatment and prevention of the resulting diseases remain a major health and research concern. The arbovirus infection and replication processes are complex, and many factors are involved in their regulation. Apoptosis, autophagy and the unfolded protein response (UPR) are three mechanisms that are involved in pathogenesis of many viruses. In this review, we focus on the importance of these pathways in the arbovirus replication and infection processes. We provide a brief introduction on how apoptosis, autophagy and the UPR are initiated and regulated, and then discuss the involvement of these pathways in regulation of arbovirus pathogenesis.

  • 12.
    Jangamreddy, Jaganmohan
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Ghavami, Saeid
    University of Manitoba, Winnipeg, Canada.
    Grabarek, Jerzy
    Pomeranian Medical University, Szczecin, Poland.
    Kratz, Gunnar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Regenerativ medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Sinnescentrum, Hand- och plastikkirurgiska kliniken US.
    Wiechec, Emilia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Regenerativ medicin. Linköpings universitet, Hälsouniversitetet.
    Fredriksson, Bengt-Arne
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Rao, Rama K.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Cieślar-Pobuda, Artur
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Regenerativ medicin. Linköpings universitet, Hälsouniversitetet.
    Panigrahi, Soumya
    Lerner Research Institute, Cleveland, OH, USA.
    Łos, Marek
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Regenerativ medicin. Linköpings universitet, Hälsouniversitetet.
    Salinomycin induces activation of autophagy, mitophagy and affects mitochondrial polarity: Differences between primary and cancer cells2013Inngår i: Biochimica et Biophysica Acta. Molecular Cell Research, ISSN 0167-4889, E-ISSN 1879-2596, Vol. 1833, nr 9, s. 2057-2069Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The molecular mechanism of Salinomycin's toxicity is not fully understood. Various studies reported that Ca2 +, cytochrome c, and caspase activation play a role in Salinomycin-induced cytotoxicity. Furthermore, Salinomycin may target Wnt/β-catenin signaling pathway to promote differentiation and thus elimination of cancer stem cells. In this study, we show a massive autophagic response to Salinomycin (substantially stronger than to commonly used autophagic inducer Rapamycin) in prostrate-, breast cancer cells, and to lesser degree in human normal dermal fibroblasts. Interestingly, autophagy induced by Salinomycin is a cell protective mechanism in all tested cancer cell lines. Furthermore, Salinomycin induces mitophagy, mitoptosis and increased mitochondrial membrane potential (∆Ψ) in a subpopulation of cells. Salinomycin strongly, and in time-dependent manner decreases cellular ATP level. Contrastingly, human normal dermal fibroblasts treated with Salinomycin show some initial decrease in mitochondrial mass, however they are largely resistant to Salinomycin-triggered ATP-depletion. Our data provide new insight into the molecular mechanism of preferential toxicity of Salinomycin towards cancer cells, and suggest possible clinical application of Salinomycin in combination with autophagy inhibitors (i.e. clinically-used Chloroquine). Furthermore, we discuss preferential Salinomycins toxicity in the context of Warburg effect.

  • 13.
    Johnston, James B.
    et al.
    University of Manitoba,Winnipeg, MB,R3E 0V9, Canada.
    Navaratnam, Sri
    University of Manitoba,Winnipeg, MB,R3E 0V9, Canada.
    Pitz, Marshall W.
    University of Manitoba,Winnipeg, MB,R3E 0V9, Canada.
    Maniate, Jerry M.
    University of Manitoba,Winnipeg, MB,R3E 0V9, Canada.
    Wiechec, Emilia
    Manitoba Institute of Cell Biology, CancerCare Manitoba.
    Baust, Heinrich
    University of Manitoba,Winnipeg, MB,R3E 0V9, Canada.
    Gingerich, Joel
    University of Manitoba,Winnipeg, MB,R3E 0V9, Canada.
    Skliris, Georgios P.
    University of Manitoba,Winnipeg, MB,R3E 0V9, Canada.
    Murphy, Leigh C.
    University of Manitoba,Winnipeg, MB,R3E 0V9, Canada.
    Los, Marek Jan
    Manitoba Institute of Cell Biology, Cancer Care Manitoba; Manitoba Institute of Child Health; Department of Biochemistry and Medical Genetics; Department of Human Anatomy and Cell Science, University Manitoba, Winnipeg, Canada, .
    Targeting the EGFR pathway for cancer therapy2006Inngår i: Current Medicinal Chemistry, ISSN 0929-8673, E-ISSN 1875-533X, Vol. 13, nr 29, s. 3483-3492Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Clinical studies have shown that HER-2/Neu is over-expressed in up to one-third of patients with a variety of cancers, including B-cell acute lymphoblastic leukemia (B-ALL), breast cancer and lung cancer, and that these patients are frequently resistant to conventional chemo-therapies. Additionally, in most patients with multiple myeloma, the malignant cells over-express a number of epidermal growth factor receptors (EGFR)s and their ligands, HB-EGF and amphiregulin, thus this growth-factor family may be an important aspect in the patho-biology of this disease. These and other, related findings have provided the rationale for the targeting of the components of the EGFR signaling pathways for cancer therapy. Below we discuss various aspects of EGFR-targeted therapies mainly in hematologic malignancies, lung cancer and breast cancer. Beside novel therapeutic approaches, we also discuss specific side effects associated with the therapeutic inhibition of components of the EGFR-pathways. Alongside small inhibitors, such as Lapatinib (Tykerb, GW572016), Gefitinib (Iressa, Z131839), and Erlotinib (Tarceva, OSI-774), a significant part of the review is also dedicated to therapeutic antibodies (e.g.: Trastuzumab / Herceptin, Pertuzumab / Omnitarg / rhuMab-2C4, Cetuximab / Erbitux / IMC-C225, Panitumumab / Abenix / ABX-EGF, and also ZD6474). In addition, we summarize, both current therapy development driven by antibody-based targeting of the EGFR-dependent signaling pathways, and furthermore, we provide a background on the history and the development of therapeutic antibodies.

  • 14.
    Kashefi-Kheyrabadi, Leila
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biosensorer och bioelektronik. Linköpings universitet, Tekniska högskolan. University of Isfahan, Iran.
    Mehrgardi, Masoud
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biosensorer och bioelektronik. Linköpings universitet, Tekniska högskolan. University of Isfahan, Iran.
    Wiechec, Emilia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Turner, Anthony P.F.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biosensorer och bioelektronik. Linköpings universitet, Tekniska högskolan.
    Tiwari, Ashutosh
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biosensorer och bioelektronik. Linköpings universitet, Tekniska högskolan.
    Ultrasensitive detection of human liver hepatocellular carcinoma (HepG2) cells using a label-free aptasensor2014Inngår i: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 86, nr 10, s. 4956-4960Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Liver cancer is one of the most common cancers in the world and has no effective cure, especially in later stages. The development of a tangible protocol for early diagnosis of this disease remains a major challenge. In the present manuscript, an aptamer-based, label-free electrochemical biosensor for the sensitive detection of HepG2, a hepatocellular carcinoma cell line, is described. The target cells are captured in a sandwich architecture using TLS11a aptamer covalently attached to a gold surface and a secondary TLS11a aptamer. The application of TLS11a aptamer as a recognition layer resulted in a sensor with high affinity for HepG2 cancer cells in comparison with control cancer cells of human prostate, breast and colon tumours. The aptasensor delivered a wide linear dynamic range over 1 × 102 – 1 × 106 cell/mL, with a detection limit of 2 cell/mL. This protocol provides a precise method for sensitive detection of liver cancer with significant advantages in terms of simplicity, low cost, and stability.

  • 15.
    Klonisch, Thomas
    et al.
    Department of Human Anatomy and Cell Sciences, Winnipeg, Canada.
    Wiechec, Emilia
    Manitoba Institute of Cell Biology, CancerCare Manitoba; Department of Human Genetics, University of Aarhus, Aarhus, Denmark.
    Hombach-Klonisch, Sabine
    Department of Human Anatomy and Cell Science, University of Manitoba, Winnipeg, R3E 0W3, MB, Canada.
    Ande, Sudharsana R.
    Manitoba Institute of Cell Biology, CancerCare Manitoba, Winnipeg, R3E 0V9, MB, Canada; Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, R3E 0W3, MB, Canada.
    Wesselborg, Sebastian
    Department of Internal Medicine I, University of Tübingen, D-72076 Tübingen, Germany.
    Schulze-Osthoff, Klaus
    Interfaculty Institute for Biochemistry, University of Tübingen, Germany.
    Los, Marek Jan
    University of Manitoba, Winnipeg, Canada.
    Cancer stem cell markers in common cancers - therapeutic implications2008Inngår i: Trends in Molecular Medicine, ISSN 1471-4914, E-ISSN 1471-499X, Vol. 14, nr 10, s. 450-460Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Rapid advances in the cancer stem cell (CSC) field have provided cause for optimism for the development of more reliable cancer therapies in the future. Strategies aimed at efficient targeting of CSCs are becoming important for monitoring the progress of cancer therapy and for evaluating new therapeutic approaches. Here, we characterize and compare the specific markers that have been found to be present on stem cells, cancer cells and CSCs in selected tissues (colon, breast, liver, pancreas and prostate). We then discuss future directions of this intriguing new research field in the context of new diagnostic and therapeutic opportunities.

  • 16.
    Lacoste, Sandrine
    et al.
    University of Manitoba, Winnipeg, Canada.
    Wiechec, Emilia
    University of Aarhus, Denmark.
    Dos Santos Silva, Amanda
    Unversity of Sao Paulo, Brazil.
    Guffei, Amanda
    University of Manitoba, Winnipeg, Canada.
    Williams, G
    Lowbeer, M
    Benedek, K
    Henriksson, M
    Klein, George
    Mai, Sabine
    University of Manitoba, Winnipeg, Canada.
    Chromosomal rearrangements after ex vivo Epstein–Barr virus (EBV) infection of human B cellsEBV infection-mediated genomic instability in B cells2010Inngår i: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 29, s. 503-515Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The Epstein–Barr virus (EBV) is carried by more than 90% of the adult world population and has been implicated in several human malignancies. Its ability to induce unlimited in vitro proliferation of B cells is frequently used to generate lymphoblastoid cell lines (LCLs). In this study, we have investigated the evolution of two LCLs up to 25 weeks after EBV infection. LCLs were karyotyped once a month by spectral karyotyping (SKY). LCLs but not mitogen-activated B cells showed evidence of DNA damage and DNA damage response within the first 2 weeks. After 4 weeks, the former, but not the latter, showed a high level of non-clonal structural aberrations, mainly deletions, fragments, dicentric chromosomes and unbalanced translocations. Genomic instability decreased thereafter over time. Nonrandom aneuploidy 12 weeks after infection showed clonal evolution in culture. After 25 weeks post-infection, most cells exhibited karyotypic stability. Chromosomal aberrations were compatible with telomere dysfunction, although in the absence of telomere shortening. The telomere capping protein TRF2 was partially displaced from telomeres in EBV-infected cells, suggesting an EBV-mediated uncapping problem. In conclusion, this study suggests that DNA damage and telomere dysfunction contribute to EBV-related chromosomal instability in early LCLs.

  • 17.
    Maddika, Subbareddy
    et al.
    Manitoba Institute of Cell Biology, Cancer Care Manitoba; Department of Biochemistry and Medical Genetics,University of Manitoba, Winnipeg, Canada .
    Ande, Sudharsana Rao
    Manitoba Institute of Cell Biology, CancerCare Manitoba, University of Manitoba, Winnipeg, Canada.
    Panigrahi, Soumya
    Department of Physiology, University of Manitoba, Winnipeg, Canada; Manitoba Institute of Cell Biology, CancerCare Manitoba, University of Manitoba, Winnipeg, Manitoba, Canada, .
    Paranjothy, Ted
    Manitoba Institute of Cell Biology, CancerCare Manitoba, University of Manitoba, Winnipeg, Canada.
    Weglarczyk, Kazimierz
    Manitoba Institute of Cell Biology, CancerCare Manitoba, University of Manitoba, Winnipeg, Canada; Department of Clinical Immunology, Polish-American Institute of Pediatrics, Jagiellonian University Medical College, Krakow, Poland.
    Zuse, Anne
    Manitoba Institute of Cell Biology, CancerCare Manitoba, University of Manitoba, Winnipeg, Canada.
    Eshraghi, Mehdi
    Manitoba Institute of Cell Biology, CancerCare Manitoba, University of Manitoba, Winnipeg, Canada; Manitoba Institute of Cell Biology, and Department of Biochemistry and Medical Genetics, Univ. Manitoba, Winnipeg, Canada; D.
    Manda, Kamala D.
    Department of Immunology, University of Manitoba, Winnipeg, Canada.
    Wiechec, Emilia
    Manitoba Institute of Cell Biology, CancerCare Manitoba; Department of Human Genetics, University of Aarhus, Aarhus, Denmark,.
    Los, Marek Jan
    Manitoba Institute of Cell Biology, Cancer Care Manitoba; Manitoba Institute of Child Health; Department of Biochemistry and Medical Genetics; Department of Human Anatomy and Cell Science, University Manitoba, Winnipeg, Canada, .
    Cell survival, cell death and cell cycle pathways are interconnected: Implications for cancer therapy2007Inngår i: Drug resistance updates, ISSN 1368-7646, E-ISSN 1532-2084, Vol. 10, nr 1-2, s. 13-29Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The partial cross-utilization of molecules and pathways involved in opposing processes like cell survival, proliferation and cell death, assures that mutations within one signaling cascade will also affect the other opposite process at least to some extent, thus contributing to homeostatic regulatory circuits. This review highlights some of the connections between opposite-acting pathways. Thus, we discuss the role of cyclins in the apoptotic process, and in the regulation of cell proliferation. CDKs and their inhibitors like the INK4-family (p16(Ink4a), p15(Ink4b), P18(Ink4c), p19(Ink4d)), and the Cip1/Waf1/Kip1-2-family (p21(Cip1/Waf1), p27(Kip1), p57(Kip2)) are shown both in the context of proliferation regulators and as contributors to the apoptotic machinery. Bc12-family members (i.e. Bcl2, Bcl-X-L Mcl-1(L); Bax, Bok/Mtd, Bak, and Bcl-X-S; Bad, Bid, Bim(EL), Bmf, Mcl-1(S)) are highlighted both for their apoptosis-regulating capacity and also for their effect on the cell cycle progression. The PI3-K/Akt cell survival pathway is shown as regulator of cell metabolism and cell survival, but examples are also provided where aberrant activity of the pathway may contribute to the induction of apoptosis. Myc/Mad/Max proteins are shown both as a powerful S-phase driving complex and as apoptosis-sensitizers. We also discuss multifunctional proteins like p53 and Rb (RBL1/p107, RBL2/p130) both in the context of G(1)-S transition and as apoptotic triggers. Finally, we reflect on novel therapeutic approaches that would involve redirecting over-active survival and proliferation pathways towards induction of apoptosis in cancer cells. (c) 2007 Elsevier Ltd. All rights reserved.

  • 18.
    Maddika, Subbareddy
    et al.
    Manitoba Institute of Cell Biology, CancerCare Manitoba, University of Manitoba, Winnipeg, MB, R3E 0V9, Canada; Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, MB, Canada.
    Ande, Sudharsana Rao
    Manitoba Institute of Cell Biology, CancerCare Manitoba, University of Manitoba, Winnipeg, MB, R3E 0V9, Canada.
    Wiechec, Emilia
    Manitoba Institute of Cell Biology, CancerCare Manitoba; Department of Human Genetics, University of Aarhus, Aarhus, Denmark; Department of Experimental and Clinical Radiobiology, Oncology Center, Maria Sklodowka-Curie Memorial Institute, Wybrzeze Armii Krajowej 15, PL-44100 Gliwice, Poland .
    Hansen, Lise Lotte
    Department of Experimental and Clinical Radiobiology, Oncology Center, Maria Sklodowka-Curie Memorial Institute, Wybrzeze Armii Krajowej 15, PL-44100 Gliwice, Poland .
    Wesselborg, Sebastian
    Department of Internal Medicine I, University of Tübingen, Tübingen, Germany.
    Los, Marek Jan
    BioApplications Enterprises, Winnipeg, MB, Canada; Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, MB, R3E 0V9, Canada; Manitoba Institute of Cell Biology, CancerCare Manitoba, University of Manitoba, Winnipeg, MB, R3E 0V9, Canada .
    Akt-mediated phosphorylation of CDK2 regulates its dual role in cell cycle progression and apoptosis2008Inngår i: Journal of Cell Science, ISSN 0021-9533, E-ISSN 1477-9137, Vol. 121, s. 979-988Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Here, we show that CDK2, an S-phase cyclin-dependent kinase, is a novel target for Akt during cell cycle progression and apoptosis. Akt phosphorylates CDK2 at threonine 39 residue both in vitro and in vivo. Although CDK2 threonine 39 phosphorylation mediated by Akt enhances cyclin-A binding, it is dispensable for its basal binding and the kinase activity. In addition, for the first time, we report a transient nucleo-cytoplasmic shuttling of Akt during specific stages of the cell cycle, in particular during the late S and G2 phases. The Akt that is re-localized to the nucleus phosphorylates CDK2 and causes the temporary cytoplasmic localization of the CDK2–cyclin-A complex. The CDK2 cytoplasmic redistribution is required for cell progression from S to G2-M phase, because the CDK2 T39A mutant, which lacks the phosphorylation site and is defective in cytoplasmic localization, severely affects cell cycle progression at the transition from S to G2-M. Interestingly, we also show that the Akt/CDK2 pathway is constitutively activated by some anticancer drugs, such as methotrexate and docetaxel, and under these conditions it promotes, rather than represses, cell death. Thus, the constitutive activation of the Akt/CDK2 pathway and changed subcellular localization promotes apoptosis. By contrast, the transient, physiological Akt/CDK2 activation is necessary for cell cycle progression.

  • 19.
    Maddika, Subbareddy
    et al.
    Manitoba Institute of Cell Biology, Cancer Care Manitoba; Department of Biochemistry and Medical Genetics.
    Bay, G. H.
    Manitoba Institute of Cell Biology, Cancer Care Manitoba.
    Kroczak, T. J.
    Manitoba Institute of Cell Biology, Cancer Care Manitoba.
    Ande, Sudharsana R
    Manitoba Institute of Cell Biology, Cancer Care Manitoba; Department of Biochemistry and Medical Genetics .
    Wiechec, Emilia
    Manitoba Institute of Cell Biology, CancerCare Manitoba; Department of Human Genetics, University of Aarhus, Aarhus, Denmark,.
    Gibson, S. B.
    Manitoba Institute of Cell Biology, Cancer Care Manitoba; Manitoba Institute of Child Health; Department of Biochemistry and Medical Genetics, .
    Los, Marek Jan
    BioApplications Enterprises, Winnipeg, MB, Canada; Manitoba Institute of Cell Biology, Cancer Care Manitoba; Manitoba Institute of Child Health; Department of Biochemistry and Medical Genetics; Department of Human Anatomy and Cell Science, University Manitoba, Winnipeg, Canada, .
    Akt is transferred to the nucleus of cells treated with apoptin, and it participates in apoptin-induced cell death2007Inngår i: Cell Proliferation, ISSN 0960-7722, E-ISSN 1365-2184, Vol. 40, nr 6, s. 835-848Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Abstract. Objectives: The phosphatidylinositol 3-kinase (PI3-K)/Akt pathway is well known for the regulation of cell survival, proliferation, and some metabolic routes. Meterials and Methods: In this study, we document a novel role for the PI3-K/Akt pathway during cell death induced by apoptin, a tumour-selective inducer of apoptosis. Results: We show for the first time that apoptin interacts with the p85 regulatory subunit, leading to constitutive activation of PI3-K. The inhibition of PI3-K activation either by chemical inhibitors or by genetic approaches severely impairs cell death induced by apoptin. Downstream of PI3-K, Akt is activated and translocated to the nucleus together with apoptin. Direct interaction between apoptin and Akt is documented. Co-expression of nuclear Akt significantly potentiates cell death induced by apoptin. Thus, apoptin-facilitated nuclear Akt, in contrast to when in its cytoplasmic pool, appears to be a positive regulator, rather than repressor of apoptosis. Conclusions: Our observations indicate that PI3-K/Akt pathways have a dual role in both survival and cell death processes depending on the stimulus. Nuclear Akt acts as apoptosis stimulator rather than as a repressor, as it likely gains access to a new set of substrates in the nucleus. The implicated link between survival and cell death pathways during apoptosis opens new pharmacological opportunities to modulate apoptosis in cancer, for example through the manipulation of Akt's cellular localization.

  • 20.
    Maddika, Subbareddy
    et al.
    Manitoba Institute of Cell Biology, CancerCare Manitoba; Department of Biochemistry and Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Canada .
    Panigrahi, Soumya
    Manitoba Institute of Cell Biology, CancerCare Manitoba; Department of Biochemistry and Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Canada .
    Wiechec, Emilia
    Manitoba Institute of Cell Biology, CancerCare Manitoba; Department of Human Genetics, University of Aarhus, Aarhus, Denmark.
    Wesselborg, Sebastian
    Department of Internal Medicine, University of Tübingen, Tübingen, Germany.
    Fischer, Ute
    Interfaculty Institute for Biochemistry, University of Tübingen, D-72076 Tübingen, Germany; Institute of Molecular Medicine, University of Düsseldorf, D-40225 Düsseldorf, Germany.
    Schulze-Osthoff, Klaus
    Interfaculty Institute for Biochemistry, University of Tübingen, Germany.
    Los, Marek Jan
    Interfaculty Institute for Biochemistry, University of Tübingen, Germany; BioApplications Enterprises, Winnipeg, MB, Canada.
    Unscheduled Akt-Triggered Activation of Cyclin-Dependent Kinase 2 as a Key Effector Mechanism of Apoptin's Anticancer Toxicity2009Inngår i: Molecular and Cellular Biology, ISSN 0270-7306, E-ISSN 1098-5549, Vol. 29, nr 5, s. 1235-1248Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Apoptin, a protein from the chicken anemia virus, has attracted attention because it specifically kills tumor cells while leaving normal cells unharmed. The reason for this tumor selectivity is unclear and depends on subcellular localization, as apoptin resides in the cytoplasm of normal cells but in the nuclei of transformed cells. It was shown that nuclear localization and tumor-specific killing crucially require apoptin's phosphorylation by an as yet unknown kinase. Here we elucidate the pathway of apoptin-induced apoptosis and show that it essentially depends on abnormal phosphatidylinositol 3-kinase (PI3-kinase)/Akt activation, resulting in the activation of the cyclin-dependent kinase CDK2. Inhibitors as well as dominant-negative mutants of PI3-kinase and Akt not only inhibited CDK2 activation but also protected cells from apoptin-induced cell death. Akt activated CDK2 by direct phosphorylation as well as by the phosphorylation-induced degradation of the inhibitor p27Kip1. Importantly, we also identified CDK2 as the principal kinase that phosphorylates apoptin and is crucially required for apoptin-induced cell death. Immortalized CDK2-deficient fibroblasts and CDK2 knockdown cells were markedly protected against apoptin. Thus, our results not only decipher the pathway of apoptin-induced cell death but also provide mechanistic insights for the selective killing of tumor cells.

  • 21.
    Maddika, Subbareddy
    et al.
    Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada; Manitoba Institute of Cell Biology, CancerCare Manitoba, University of Manitoba, Winnipeg, Manitoba, Canada; Department of Therapeutic Radiology, Yale School of Medicine, New Haven, USA.
    Wiechec, Emilia
    Manitoba Institute of Cell Biology, CancerCare Manitoba; Department of Human Genetics, University of Aarhus, Aarhus, Denmark,.
    Ande, S. R.
    Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada; Manitoba Institute of Cell Biology, CancerCare Manitoba, University of Manitoba, Winnipeg, Manitoba, Canada.
    Poon, I. K.
    Nuclear Signaling Laboratory, Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.
    Fischer, Ute
    Institute of Molecular Medicine, University of Düsseldorf, Düsseldorf, Germany.
    Wesselborg, Sebastian
    Department of Internal Medicine I, University of Tübingen, Tübingen, Germany; and BioApplications Enterprises, Winnipeg, Manitoba, Canada.
    Jans, D. A.
    Nuclear Signaling Laboratory, Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.
    Schulze-Osthoff, Klaus
    Institute of Molecular Medicine, University of Düsseldorf, Düsseldorf, Germany .
    Los, Marek Jan
    BioApplications Enterprises, Winnipeg, MB, Canada; Department of Human Anatomy and Cell Science, University of Manitoba, Winnipeg, Manitoba, Canada; Manitoba Institute of Child Health, University of Manitoba, Winnipeg, Manitoba, Canada.
    Interaction with PI3-kinase contributes to the cytotoxic activity of Apoptin2008Inngår i: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 27, s. 3060-3065Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Apoptin, a small protein from the chicken anemia virus, has attracted attention because of its specificity in killing tumor cells. Localization of apoptin in the nucleus of tumor cells has been shown to be vital for proapoptotic activity, however, targeted expression of apoptin in the nucleus of normal cells does not harm the cells, indicating that nuclear localization of apoptin is insufficient for its cytotoxicity. Here, we demonstrate for the first time that apoptin interacts with the SH3 domain of p85, the regulatory subunit of phosphoinositide 3-kinase (PI3-K), through its proline-rich region. Apoptin derivatives devoid of this proline-rich region do not interact with p85, are unable to activate PI3-K, and show impaired apoptosis induction. Moreover, apoptin mutants containing the proline-rich domain are sufficient to elevate PI3-K activity and to induce apoptosis in cancer cells. Downregulation of p85 leads to nuclear exclusion of apoptin and impairs cell death induction, indicating that interaction with the p85 PI3-K subunit essentially contributes to the cytotoxic activity of apoptin.

  • 22.
    Melissaridou, Styliani
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Wiechec, Emilia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Magan, Mustafa
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Jain, Mayur Vilas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Department of Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, Lund, Sweden.
    Chung, Man Ki
    Department of Otorhinolaryngology-Head & Neck Surgery, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, South Korea.
    Farnebo, Lovisa
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Öron- näsa- och halskliniken US.
    Roberg, Karin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Öron- näsa- och halskliniken US.
    The effect of 2D and 3D cell cultures on treatment response, EMT profile and stem cell features in head and neck cancer.2019Inngår i: Cancer Cell International, ISSN 1475-2867, E-ISSN 1475-2867, Vol. 19, nr 16Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background

    Head and Neck Squamous Cell Carcinoma (HNSCC) tumors are often resistant to therapies. Therefore searching for predictive markers and new targets for treatment in clinically relevant in vitro tumor models is essential. Five HNSCC-derived cell lines were used to assess the effect of 3D culturing compared to 2D monolayers in terms of cell proliferation, response to anti-cancer therapy as well as expression of EMT and CSC genes.

    Methods

    The viability and proliferation capacity of HNSCC cells as well as induction of apoptosis in tumor spheroids cells after treatment was assessed by MTT assay, crystal violet- and TUNEL assay respectively. Expression of EMT and CSC markers was analyzed on mRNA (RT-qPCR) and protein (Western blot) level.

    Results

    We showed that HNSCC cells from different tumors formed spheroids that differed in size and density in regard to EMT-associated protein expression and culturing time. In all spheroids, an up regulation of CDH1, NANOG and SOX2 was observed in comparison to 2D but changes in the expression of EGFR and EMT markers varied among the cell lines. Moreover, most HNSCC cells grown in 3D showed decreased sensitivity to cisplatin and cetuximab (anti-EGFR) treatment.

    Conclusions

    Taken together, our study points at notable differences between these two cellular systems in terms of EMT-associated gene expression profile and drug response. As the 3D cell cultures imitate the in vivo behaviour of neoplastic cells within the tumor, our study suggest that 3D culture model is superior to 2D monolayers in the search for new therapeutic targets.

  • 23.
    Patra, Hirak Kumar
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biosensorer och bioelektronik. Linköpings universitet, Tekniska högskolan.
    Khaliq, Nisar Ul
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biosensorer och bioelektronik. Linköpings universitet, Tekniska högskolan.
    Romu, Thobias
    Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV. Linköpings universitet, Institutionen för medicinsk teknik, Medicinsk informatik. Linköpings universitet, Tekniska högskolan.
    Wiechec, Emilia
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi.
    Borga, Magnus
    Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV. Linköpings universitet, Institutionen för medicinsk teknik, Medicinsk informatik. Linköpings universitet, Tekniska högskolan.
    Turner, Anthony P. F.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biosensorer och bioelektronik. Linköpings universitet, Tekniska högskolan.
    Tiwari, Ashutosh
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biosensorer och bioelektronik. Linköpings universitet, Tekniska högskolan.
    MRI-Visual Order–Disorder Micellar Nanostructures for Smart Cancer Theranostics2014Inngår i: Advanced Healthcare Materials, ISSN 2192-2640, Vol. 3, nr 4, s. 526-535Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The development of MRI-visual order–disorder structures for cancer nanomedicine explores a pH-triggered mechanism for theragnosis of tumor hallmark functions. Superparamagnetic iron oxide nanoparticles (SPIONs) stabilized with amphiphilic poly(styrene)-b-poly(acrylic acid)-doxorubicin with folic acid (FA) surfacing are employed as a multi-functional approach to specifically target, diagnose, and deliver drugs via a single nanoscopic platform for cancer therapy. The functional aspects of the micellar nanocomposite is investigated in vitro using human breast SkBr3 and colon cancer HCT116 cell lines for the delivery, release, localization, and anticancer activity of the drug. For the first time, concentration-dependent T2-weighted MRI contrast for a monolayer of clustered cancer cells is shown. The pH tunable order–disorder transition of the core–shell structure induces the relative changes in MRI contrast. The outcomes elucidate the potential of this material for smart cancer theranostics by delivering non-invasive real-time diagnosis, targeted therapy, and monitoring the course and response of the action before, during, and after the treatment regimen.

  • 24.
    Pedersen, Kristina
    et al.
    University of Aarhus, Denmark .
    Wiechec, Emilia
    University of Aarhus, Denmark .
    Madsen, Bo Eskerod
    University of Aarhus, Denmark .
    Overgaard, Jens
    Aarhus University Hospital, Denmark .
    Hansen, Lise Lotte
    University of Aarhus, Denmark .
    A simple way to evaluate self-designed probes for tumor specific Multiplex Ligation-dependent Probe Amplification (MLPA)2010Inngår i: BMC Research Notes, ISSN 1756-0500, E-ISSN 1756-0500, Vol. 3Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND:

    The Multiplex Ligation-dependent Probe Amplification (MLPA) is widely used for analysis of copy number variations (CNVs) in single or multiple loci. MLPA is a versatile methodology and important tool in cancer research; it provides precise information on increased or decreased copy number at specific loci as opposed to loss of heterozygosity (LOH) studies based upon microsatellite analysis. Pre-designed MLPA kits and software are commercially available to analyze multiple exons, genes, and genomic regions. However, an increasing demand for new gene specific assays makes it necessary to self-design new MLPA probes for which the available software may not be applicable. During evaluation of new self-designed reference probes, we encountered a number of problems, especially when applying the MLPA methodology to tumor samples.

    FINDINGS:

    DNA samples from 48 unaffected individuals and 145 breast cancer patients were used to evaluate 11 self-designed MLPA probes and determine the cut-off values for CNV, before applying the MLPA probes to normalize the target probes in a cohort of affected individuals. To test the calculation strategy, three probes were designed to cover regions in Regulator of G-protein Signaling 8 (RGS8), which we previously have identified as being affected by allelic imbalance by LOH analysis across RGS8 in the cohort comprising 145 breast tumors. Agreement between the LOH results and the results obtained by each of the three MLPA probes in RGS8 was found for 64%, 73%, and 91%, of the analyzed samples, respectively.

    CONCLUSION:

    Here, we present a straightforward method, based upon the normalization pattern in both unaffected and affected individuals, to evaluate self-designed reference probes and to calculate CNV for the MLPA assay with specific focus on the difficulties when analyzing tumor DNA.

  • 25.
    Skonieczna, Magdalena
    et al.
    Silesian University of Technology.
    Cieslar-Pobuda, Artur
    Centre for Molecular Medicine, Norway .
    Saenko, Yuriy
    S.P.Kapitsa Technological Research Institute.
    Foksinski, Marek
    Collegium Medicum in Bydgoszcz, Poland.
    Olinski, Ryszard
    Collegium Medicum in Bydgoszcz, Poland.
    Rzeszowska-Wolny, Joanna
    Silesian University of Technology, Poland.
    Wiechec, Emilia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Logopedi, Audiologi och Otorhinolaryngologi. Linköpings universitet, Medicinska fakulteten.
    The impact of DIDS-induced inhibition of voltage-dependent anion channels (VDAC) on cellular response of lymphoblastoid cells to ionizing radiation.2017Inngår i: Medicinal chemistry, ISSN 1573-4064, Vol. 13, nr 5, s. 477-483Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: The voltage-dependent ion channels (VDAC) play an essential role in the cross talk between mitochondria and the rest of the cell. Their implication in cell life and cell death has been studied extensively in recent years. In this work we studied the impact of mitochondrial membrane voltage-dependent anion channels (VDACs) on cell survival and response to X-ionizing radiation (IR) of human lymphoblastoid K562 cells. Methods: The inhibition of VDACs was achieved by 4,4′-diisothiocyanostilbene-2,2′-disulfonic acid (DIDS) inhibitor and in vitro experiments including clonogenity assay, UV-visible spectrophotometry, comet assay and FACS analysis were implemented. Results: Inhibition of VDAC led to augmentation of IR-induced apoptosis and ROS production. Additionally, DIDS affected repair of IR-induced DNA strand breaks and was in line with both induction of apoptosis and caspase activity. The IR-induced NO production was potently reduced by inhibition of VDAC. Conclusion: Our results suggest that VDAC control cellular response to ionizing radiation through modulation of the ROS- and NO-dependent signaling pathways. Inhibition of VDAC with DIDS induced apoptosis in irradiated K562 lymphoblastoid cells points at DIDS, as a promising agent to enhance the effectiveness of radiotherapy.

  • 26.
    Wiechec, Emilia
    Otto-von-Guericke University, Magdeburg, Germany.
    Implications of genomic instability in the diagnosis and treatment of breast cancer2011Inngår i: Expert Review of Molecular Diagnostics, ISSN 1473-7159, E-ISSN 1744-8352, Vol. 11, nr 4, s. 445-453Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Tumorigenesis is a multistep process resulting from DNA mutations observed at the DNA sequence and chromosome level as well as epigenetic changes, which affect expression of oncogenes and tumor suppressor genes. Breast cancer is a very heterogeneous disease that manifests in various histological and clinical types. Defects in the biological action of the genome driven by various alterations, such as point mutations and chromosomal rearrangements, lead to the collapse of genome integrity, uncontrolled cell proliferation and failure in apoptotic cell death. Detailed profiling of breast cancer-associated genomic alterations is indispensable for the design of individualized anticancer therapy, by suggesting diagnostic and prognostic criteria as well as the outcome of applied treatment. Among various directions of cancer research, identification of genomic alterations in breast cancer and their translation into clinical applications is at the forefront.

  • 27.
    Wiechec, Emilia
    et al.
    University of Aarhus, Denmark.
    Hansen, Lise Lotte
    University of Aarhus, Denmark.
    The effect of genetic variability on drug response in conventional breast cancer treatment2009Inngår i: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 625, nr 1-3, s. 122-130Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    The conventional breastcancer diagnosis based mainly upon histopathology, hormone and HER-2 receptor status, will in the future be combined with information on genomic and epigenetic profiles of the individual patient. This will lead to an optimal personalized therapy, directed towards specific genomic aberrations, avoiding unnecessary toxicity, side effects and chemotherapeutic drugs for which the patient evolves resistance. Breastcancer is a very heterogeneous malignancy, expressing a considerable variation in genomic aberrations from deletions and amplifications comprising entire chromosomes to minor regions. A wide spectrum of differently expressed genes and mutations has been identified, adding information to the highly complex picture of the tumor genome. The vast majority of breastcancer incidents is of somatic origin and may be caused by a combination of the individual genetic profile and environmental exposure. A major contributor to the variation in genetic profile is the single nucleotide polymorphisms (SNPs), which are highly abundant throughout the genome, and both current and future methodologies have the potential to screen millions of SNP genotypes in one analysis. Identification of specific SNP genotypes affecting transcriptional activity and thereby the outcome for the patient, of genes involved in DNA repair, metabolizing of chemotherapeutic drugs and drug target genes will determine the outcome for the patient. This will be an essential part of the development of personalized treatment of cancer. In this review the focus is on clinically relevant SNPs in genes implicated in drug metabolism and disposition as well as their influence on breastcancer therapy toxicity and/or efficacy.

  • 28.
    Wiechec, Emilia
    et al.
    Danish Centre for Molecular Gerontology, Institute of Human Genetics, University of Aarhus, Denmark.
    Overgaard, Jens
    Aarhus University Hospital, Denmark.
    Hansen, Lise-Lotte
    Danish Centre for Molecular Gerontology, Institute of Human Genetics, University of Aarhus, Denmark.
    A fragile site within the HPC1 region at 1q25.3 affecting RGS16, RGSL1, and RGSL2 in human breast carcinomas2008Inngår i: Genes, Chromosomes and Cancer, ISSN 1045-2257, E-ISSN 1098-2264, Vol. 47, nr 9, s. 766-780Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Genomic alterations affecting chromosome arm 1q are considered to be an early event in breast carcinogenesis and are correlated with good prognosis for the patients. In the search for new breast cancer susceptibility genes, we focused on three genes from the Regulator of G protein Signaling family clustered on 1q25.3 within the HPC1 region. RGS16, RGSL2, and RGSL1 encode proteins interacting with G proteins and accelerating termination of the G protein signaling. To evaluate the implication of these genes in somatic breast cancer, we analyzed a 154-kb segment at 1q25.3 using allelic imbalance (AI) mapping. A panel of 222 patients diagnosed with primary breast cancer was analyzed using newly identified, intragenic short tandem repeats (STRs). A high rate of AI (>50%) was found across the region and led to the identification of internal chromosomal breakpoints. A detailed mapping of the breakpoints revealed intragenic microdeletions affecting the coding regions of RGSL2, RGSL1, and the regulatory region of RGS16. The promoter region of RGS16 was found to be methylated in 10% of the tumors. A decrease in the RGS16 expression was found in tumors with chromosomal breakpoints, AI, and aberrant methylation. We found a significant association between AI of RGSL2 and localized disease, which correlated with good prognosis for patients with breast cancer. In conclusion, we found the 1q25.3 region to be highly unstable in breast tumors comprising a cluster of chromosomal breakpoints, intragenic microdeletions, frequent allelic imbalance correlating with long metastasis-free survival, and RGS16 promoter methylation affecting the protein expression.

  • 29.
    Wiechec, Emilia
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Overgaard, Jens
    Aarhus University, Denmark.
    Kjeldsen, E
    Aarhus University, Denmark.
    Hansen, Lise-Lotte
    Aarhus University, Denmark.
    Chromosome 1q25.3 copy number alterations in primary breast cancers detected by multiplex ligation-dependent probe amplification and allelic imbalance assays and its comparison with fluorescent in situ hybridization assays2013Inngår i: Cellular Oncology, ISSN 2211-3428, E-ISSN 2211-3436, Vol. 36, nr 2, s. 113-120Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Breast cancer is characterized by a complex pattern of chromosomal alterations, which is in accordance with its heterogeneous character. Simultaneous gains of 1q and losses of 16q represent early events in breast tumourigenesis and have been related to clinical outcome. Here, we evaluated the accuracy of 1q25.3 copy number detection in conjunction with allelic imbalance (AI) detection in a series of primary breast tumours.

    METHODS:

    We compared previously obtained AI results from the 1q25.3 region in a series of 222 primary breast tumours with newly obtained MLPA and FISH results. To this end, a novel 1q25.3 MLPA probe set was designed and a commercially available 1q25.3/1p35.2 dual color FISH probe set was used.

    RESULTS:

    MLPA revealed 1q25.3 copy number gains and copy number losses in subsets of the tumour samples tested. Next, tumour samples were examined by FISH and scored for the level of 1q25.3 alterations. Non-tumourigenic nuclei from healthy individuals were used to establish cut-off levels for 1q25.3 copy numbers. By doing so, we found a 100 % concordance between the FISH results in breast tumour samples displaying similar 1q25.3 copy number alterations as determined by MLPA and, previously, AI. Furthermore, FISH was found to be instrumental in determining 1q25.3 copy number alterations in samples exhibiting discordances between AI and MLPA.

    CONCLUSIONS:

    This study shows that both AI and MLPA assays can be employed to map regions exhibiting copy number alterations in cancer genomes, and that the results obtained are in concordance with FISH assays.

  • 30.
    Wiechec, Emilia
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Tiefenböck Hansson, Katharina
    Region Östergötland, Sinnescentrum, Öron- näsa- och halskliniken US.
    Alexandersson, Lisa
    Region Östergötland, Sinnescentrum, Öron- näsa- och halskliniken US.
    Jönsson, Jan-Ingvar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten.
    Roberg, Karin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Öron- näsa- och halskliniken US.
    Hypoxia Mediates Differential Response to Anti-EGFR Therapy in HNSCC Cells.2017Inngår i: International Journal of Molecular Sciences, ISSN 1422-0067, E-ISSN 1422-0067, Vol. 18, nr 5Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Despite advances in the head and neck squamous cell carcinoma (HNSCC) treatment modalities, drug resistance and cancer recurrence are often reported. Hypoxia signaling through hypoxia-inducible factor 1 (HIF-1) promotes angiogenesis and metastasis by inducing epithelial-mesenchymal-transition (EMT). The aim of this study was to evaluate the impact of hypoxia on response to therapy as well as EMT and expression of stem cell markers in HNSCC cells. Five HNSCC cell lines (UT-SCC-2, UT-SCC-14, LK0412, LK0827, and LK0923) were selected for this study. The treatment sensitivity for radiation, cisplatin, cetuximab, and dasatinib was assessed by crystal violet assay. Gene expression of EMT and cancer stem cell (CSC) markers as well as protein level of EGFR signaling molecules were analyzed by qPCR and western blotting, respectively. Unlike UT-SCC-14 and LK0827, the LK0412 cell line became significantly more sensitive to cetuximab in hypoxic conditions. This cetuximab sensitivity was efficiently reversed after suppression of HIF-1α with siRNA. Additionally, hypoxia-induced EMT and expression of stem cell markers in HNSCC cells was partially revoked by treatment with cetuximab or knockdown of HIF-1α. In summary, our study shows that hypoxia might have a positive influence on the anti-EGFR therapy effectiveness in HNSCC. However, due to heterogeneity of HNSCC lesions, targeting HIF-1α may not be sufficient to mediate such a response. Further studies identifying a trait of hypoxia-specific response to cetuximab in HNSCC are advisable.

  • 31.
    Wiechec, Emilia
    et al.
    University of Aarhus, Denmark .
    Wiuf, Carsten
    University of Aarhus, Denmark.
    Overgaard, Jens
    Aarhus University Hospital, Denmark.
    Hansen, Lise Lotte
    University of Aarhus, Denmark .
    High-Resolution Melting Analysis for Mutation Screening of RGSL1, RGS16, and RGS8 in Breast Cancer2011Inngår i: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 20, nr 2, s. 397-407Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Identification of specific mutation targets in cancer may lead to discovery of the genes modulating cancer susceptibility and/or prognosis. The RGSL1, RGS16, and RGS8 genes within the 1q25.3 region belong to the novel family of regulators of G protein signaling (RGS) genes, which increase the GTPase activity of the G alpha subunit to attenuate signaling from the G protein-coupled receptor. We evaluated the use of high-resolution melting (HRM) to screen for mutations in the genes of interest and assess their clinical significance. Methods: The HRM analysis was used to screen 32 coding exons of RGSL1, RGS16, and RGS8 in tumors from 200 breast cancer patients. All sequence variants detected by HRM resulted in abnormal shape of the melting curves. The identified mutations and known single nucleotide polymorphisms (SNP) were subsequently confirmed by sequencing, and distribution of the SNP genotypes was determined by SNaPshot analysis. A case-control analysis of genotype frequencies was carried out. Results: We identified three tumor specific missense mutations in RGSL1 (ex6 c.664 G>A (Val222Ile), ex13 c.2262 C>G (Asp754Glu), and ex13 c.2316 C>T (Ser772Leu) in three different breast cancer patients. In addition, a total of seven known SNPs were identified in this study. Genotype distributions were not significantly different between breast cancer patients and controls. Conclusions and Impact: Identification of novel mutations within RGSL1 provides a new insight into the pathophysiology of breast cancer. Moreover, the HRM analysis represents a reliable and highly sensitive method for mutation scanning of multiple exons.

  • 32.
    Yeganeh, Behzad
    et al.
    University of Toronto, Toronto, Canada.
    Moghadam, Adel R
    Islamic Azad University, Ardabil, Iran.
    Alizadeh, Javad
    University of Manitoba, Winnipeg Canada.
    Wiechec, Emilia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Alavian, Seyed M
    Baqiyatallah Research Center for Gastroenterology and Liver Disease, Tehran, Iran.
    Hashemi, Mohammad
    Zahedan University of Medical Sciences, Zahedan, Iran.
    Geramizadeh, Bita
    Shiraz University of Medical Sciences, Shiraz, Iran.
    Samali, Afshin
    National University of Ireland Galway, Galway, Ireland.
    Lankarani, Kamran B
    Shiraz University of Medical Sciences, Shiraz, Iran.
    Post, Martin
    University of Toronto, Toronto, Canada.
    Peymani, Payam
    Shiraz University of Medical Sciences, Shiraz, Iran.
    Coombs, Kevin M
    University of Manitoba, Winnipeg, Canada.
    Ghavami, Saeid
    University of Manitoba, Winnipeg, Canada.
    Hepatitis B and C virus-induced hepatitis: apoptosis, autophagy and unfolded protein response.2015Inngår i: World Journal of Gastroenterology, ISSN 1007-9327, E-ISSN 2219-2840, Vol. 21, nr 47, s. 13225-13239Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    AIM: To investigate the co-incidence of apoptosis, autophagy, and unfolded protein response (UPR) in hepatitis B (HBV) and C (HCV) infected hepatocytes.

    METHODS: We performed immunofluorescence confocal microscopy on 10 liver biopsies from HBV and HCV patients and tissue microarrays of HBV positive liver samples. We used specific antibodies for LC3β, cleaved caspase-3, BIP (GRP78), and XBP1 to detect autophagy, apoptosis and UPR, respectively. Anti-HCV NS3 and anti-HBs antibodies were also used to confirm infection. We performed triple blind counting of events to determine the co-incidence of autophagy (LC3β punctuate), apoptosis (cleaved caspase-3), and unfolded protein response (GRP78) with HBV and HCV infection in hepatocytes. All statistical analyses were performed using SPSS software for Windows (Version 16 SPSS Inc, Chicago, IL, United States). P-values < 0.05 were considered statistically significant. Statistical analyses were performed with Mann-Whitney test to compare incidence rates for autophagy, apoptosis, and UPR in HBV- and HCV-infected cells and adjacent non-infected cells.

    RESULTS: Our results showed that infection of hepatocytes with either HBV and HCV induces significant increase (P < 0.001) in apoptosis (cleavage of caspase-3), autophagy (LC3β punctate), and UPR (increase in GRP78 expression) in the HCV- and HBV-infected cells, as compared to non-infected cells of the same biopsy sections. Our tissue microarray immunohistochemical expression analysis of LC3β in HBVNeg and HBVPos revealed that majority of HBV-infected hepatocytes display strong positive staining for LC3β. Interestingly, although XBP splicing in HBV-infected cells was significantly higher (P < 0.05), our analyses show a slight increase of XBP splicing was in HCV-infected cells (P > 0.05). Furthermore, our evaluation of patients with HBV and HCV infection based on stage and grade of the liver diseases revealed no correlation between these pathological findings and induction of apoptosis, autophagy, and UPR.

    CONCLUSION: The results of this study indicate that HCV and HBV infection activates apoptosis, autophagy and UPR, but slightly differently by each virus. Further studies are warranted to elucidate the interconnections between these pathways in relation to pathology of HCV and HBV in the liver tissue.

  • 33.
    Yeganeh, Behzad
    et al.
    University of Toronto, Canada.
    Wiechec, Emilia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Ande, Sudharsana R.
    University of Manitoba, Winnipeg, Canada.
    Sharma, Pawan
    University of Calgary, Alberta, Canada.
    Moghadam, Adel Rezaei
    Islamic Azad University, Tabriz, Iran.
    Post, Martin
    University of Toronto, Canada.
    Freed, Darren H.
    University of Manitoba, Winnipeg, Canada.
    Hashemi, Mohammad
    Zahedan University of Medical Sceinces, Iran.
    Shojaei, Shahla
    Shiraz University of Medical Sciences, Iran.
    Zeki, Amir A.
    U.C. Davis, School of Medicine, CA, USA.
    Ghavami, Saeid
    University of Manitoba, Winnipeg, Canada.
    Targeting the mevalonate cascade as a new therapeutic approach in heart disease, cancer and pulmonary disease2014Inngår i: Pharmacology and Therapeutics, ISSN 0163-7258, E-ISSN 1879-016X, Vol. 143, nr 1, s. 87-110Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    The cholesterol biosynthesis pathway, also known as the mevalonate (MVA) pathway, is an essential cellular pathway that is involved in diverse cell functions. The enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase (HMGCR) is the rate-limiting step in cholesterol biosynthesis and catalyzes the conversion of HMG-CoA to MVA.

    Given its role in cholesterol and isoprenoid biosynthesis, the regulation of HMGCR has been intensely investigated. Because all cells require a steady supply of MVA, both the sterol (i.e. cholesterol) and non-sterol (i.e. isoprenoid) products of MVA metabolism exert coordinated feedback regulation on HMGCR through different mechanisms. The proper functioning of HMGCR as the proximal enzyme in the MVA pathway is essential under both normal physiologic conditions and in many diseases given its role in cell cycle pathways and cell proliferation, cholesterol biosynthesis and metabolism, cell cytoskeletal dynamics and stability, cell membrane structure and fluidity, mitochondrial function, proliferation, and cell fate.

    The blockbuster statin drugs (‘statins’) directly bind to and inhibit HMGCR, and their use for the past thirty years has revolutionized the treatment of hypercholesterolemia and cardiovascular diseases, in particular coronary heart disease. Initially thought to exert their effects through cholesterol reduction, recent evidence indicates that statins also have pleiotropic immunomodulatory properties independent of cholesterol lowering.

    In this review we will focus on the therapeutic applications and mechanisms involved in the MVA cascade including Rho GTPase and Rho kinase (ROCK) signaling, statin inhibition of HMGCR, geranylgeranyltransferase (GGTase) inhibition, and farnesyltransferase (FTase) inhibition in cardiovascular disease, pulmonary diseases (e.g. asthma and chronic obstructive pulmonary disease (COPD)), and cancer.

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