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  • 1.
    Baxtera, Shannon A.
    et al.
    University of Manitoba, Winnipeg, Canada.
    Cheung, David Y.
    University of Manitoba, Winnipeg, Canada.
    Bocangel, Patricia
    University of Manitoba, Winnipeg, Canada.
    Kim, Hae K.
    University of Manitoba, Winnipeg, Canada.
    Herbert, Krista
    University of Manitoba, Winnipeg, Canada.
    Douville, Josette M.
    University of Manitoba, Winnipeg, Canada.
    Jangamreddy, Jaganmohan Reddy
    University of Manitoba, Winnipeg, Canada.
    Zhang, Shunzhen
    University of Manitoba, Winnipeg, Canada.
    Eisensta, David D.
    University of Manitoba, Winnipeg, Canada.
    Wigle, Jeffrey T.
    University of Manitoba, Winnipeg, Canada.
    Regulation of the lymphatic endothelial cell cycle by the PROX1 homeodomain protein2011In: Biochimica et Biophysica Acta. Molecular Cell Research, ISSN 0167-4889, E-ISSN 1879-2596, Vol. 1813, no 1, p. 201-212Article in journal (Refereed)
    Abstract [en]

    The homeobox transcription factor PROX1 is essential for the development and maintenance of lymphatic vasculature. How PROX1 regulates lymphatic endothelial cell fate remains undefined. PROX1 has been shown to upregulate the expression of Cyclin E, which mediates the G1 to S transition of the cell cycle. Here we demonstrate that PROX1 activates the mouse Cyclin E1 (Ccne1) promoter via two proximal E2F-binding sites. We have determined that the N-terminal region of PROX1 is sufficient to activate a 1-kb Ccne1 promoter, whereas the homeodomain is dispensable for activation. We have identified that the Prospero domain 1 (PD1) is required for the nuclear localization of PROX1. Our comparison of two DNA-binding-deficient constructs of PROX1 showed a cell-type-specific difference between these two proteins in both their localization and function. We demonstrated that siRNA-mediated knockdown of PROX1 in lymphatic endothelial cells decreases progression from G1 to S phase of the cell cycle. We conclude that PROX1 activates the Ccne1 promoter independent of DNA binding, and our results illustrate a novel role for PROX1 in the regulation of lymphatic endothelial cell proliferation.

  • 2.
    Czubryt, Michael P.
    et al.
    Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, and Department of Physiology, University of Manitoba, Winnipeg, Canada .
    Lamoureux, Lise
    University of Manitoba, Canada .
    Ramjiawan, Angela
    University of Manitoba, Canada .
    Abrenica, Bernard
    University of Manitoba, Canada .
    Jangamreddy, Jaganmohan Reddy
    University of Manitoba, Canada .
    Swan, Kristin
    University of Manitoba, Canada .
    Regulation of Cardiomyocyte Glut4 Expression by ZAC12010In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 285, no 22, p. 16942-16950Article in journal (Refereed)
    Abstract [en]

    The transcription factor ZAC1 is expressed in a variety of tissues including the developing heart, but its physiological role is unclear. We examined the role of ZAC1 in regulating expression of the insulin-responsive glucose transporter GLUT4 and whether ZAC1 expression is altered in cardiomyocyte hypertrophy. We demonstrated expression of Zac1 mRNA and protein in rat cardiomyocytes by PCR and Western blotting, respectively. Using a combination of chromatin immunoprecipitation and luciferase assays, we showed that ZAC1 regulates Glut4 expression via a specific binding site in the Glut4 promoter. Overexpression of ZAC1 increased Glut4 mRNA and protein expression and resulted in increased glucose uptake in cardiomyocytes as determined by a fluorescent analog uptake assay. Induction of hypertrophy by phenylephrine or isoproterenol resulted in increased Zac1 expression. We identified a novel putative promoter in the Zac1 gene and demonstrated increased binding of MEF2 to this promoter in response to hypertrophic stimulation. MEF2 regulated transactivation of the Zac1 promoter and ZAC1 protein expression. This work identifies ZAC1 as a novel and previously unknown regulator of cardiomyocyte Glut4 expression and glucose uptake. Our results also implicate MEF2 as a regulator of ZAC1 expression in response to induction of hypertrophy.

  • 3.
    Farahani, Ensieh
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Patra, Hirak Kumar
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    Jangamreddy, Jaganmohan Reddy
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Rashedi, Iran
    University of Toronto, ON, Canada.
    Kawalec, Martha
    University of Manitoba, Winnipeg, Canada .
    Rao Pariti, Rama K.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Batakis, Petros
    Linköping University, Department of Physics, Chemistry and Biology, Biology. Linköping University, The Institute of Technology.
    Wiechec, Emilia
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Cell adhesion molecules and their relation to (cancer) cell stemness2014In: Carcinogenesis, ISSN 0143-3334, E-ISSN 1460-2180, Vol. 35, no 4, p. 747-759Article, review/survey (Refereed)
    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.

  • 4.
    Ghavami, Saeid
    et al.
    University of Manitoba.
    Shojaei, Shahla
    Shiraz University of Medical Sciences.
    Yeganeh, Behzad
    University of Manitoba.
    Ande, Sudharsana R.
    University of Manitoba.
    Jangamreddy, Jaganmohan R.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Mehrpour, Maryam
    Paris Descartes University Medical School.
    Christoffersson, Jonas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Chaabane, Wiem
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Moghadam, Adel Rezaei
    Islamic Azad University.
    Kashani, Hessam H.
    University of Manitoba.
    Hashemi, Mohammad
    Zahedan University of Medical Sciences.
    Owji, Ali A.
    Shiraz University of Medical Sciences.
    Łos, Marek J
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Autophagy and Apoptosis Dysfunction in Neurodegenerative Disorders2014In: Progress in Neurobiology, ISSN 0301-0082, E-ISSN 1873-5118, Vol. 112, p. 24-49Article, review/survey (Refereed)
    Abstract [en]

    Autophagy and apoptosis are basic physiologic processes contributing to the maintenance of cellular homeostasis. Autophagy encompasses pathways that target long-lived cytosolic proteins and damaged organelles. It involves a sequential set of events including double membrane formation, elongation, vesicle maturation and finally delivery of the targeted materials to the lysosome. Apoptotic cell death is best described through its morphology. It is characterized by cell rounding, membrane blebbing, cytoskeletal collapse, cytoplasmic condensation, and fragmentation, nuclear pyknosis, chromatin condensation/fragmentation, and formation of membrane-enveloped apoptotic bodies, that are rapidly phagocytosed by macrophages or neighboring cells. Neurodegenerative disorders are becoming increasingly prevalent, especially in the Western societies, with larger percentage of members living to an older age. They have to be seen not only as a health problem, but since they are care-intensive, they also carry a significant economic burden. Deregulation of autophagy plays a pivotal role in the etiology and/or progress of many of these diseases. Herein, we briefly review the latest findings that indicate the involvement of autophagy in neurodegenerative diseases. We provide a brief introduction to autophagy and apoptosis pathways focusing on the role of mitochondria and lysosomes. We then briefly highlight pathophysiology of common neurodegenerative disorders like Alzheimer's diseases, Parkinson's disease, Huntington's disease and Amyotrophic lateral sclerosis. Then, we describe functions of autophagy and apoptosis in brain homeostasis, especially in the context of the aforementioned disorders. Finally, we discuss different ways that autophagy and apoptosis modulation may be employed for therapeutic intervention during the maintenance of neurodegenerative disorders.

  • 5.
    Jangamreddy, Jaganmohan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Ghavami, Saeid
    University of Manitoba, Winnipeg, Canada.
    Grabarek, Jerzy
    Pomeranian Medical University, Szczecin, Poland.
    Kratz, Gunnar
    Linköping University, Department of Clinical and Experimental Medicine, Regenerative Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Hand and Plastic Surgery.
    Wiechec, Emilia
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Department of Clinical and Experimental Medicine, Regenerative Medicine. Linköping University, Faculty of Health Sciences.
    Fredriksson, Bengt-Arne
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Rao, Rama K.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Cieślar-Pobuda, Artur
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Department of Clinical and Experimental Medicine, Regenerative Medicine. Linköping University, Faculty of Health Sciences.
    Panigrahi, Soumya
    Lerner Research Institute, Cleveland, OH, USA.
    Łos, Marek
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Department of Clinical and Experimental Medicine, Regenerative Medicine. Linköping University, Faculty of Health Sciences.
    Salinomycin induces activation of autophagy, mitophagy and affects mitochondrial polarity: Differences between primary and cancer cells2013In: Biochimica et Biophysica Acta. Molecular Cell Research, ISSN 0167-4889, E-ISSN 1879-2596, Vol. 1833, no 9, p. 2057-2069Article in journal (Refereed)
    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.

  • 6.
    Jangamreddy, Jaganmohan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. LV Prasad Eye Inst, India.
    Haagdorens, Michel K. C.
    Antwerp Univ Hosp, Belgium; Univ Antwerp, Belgium.
    Mirazul Islam, Mohammad Mirazul
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Lewis, Philip
    Cardiff Univ, Wales.
    Samanta, Ayan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Fagerholm, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
    Liszka, Aneta
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Kozak Ljunggren, Monika
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Buznyk, Oleksiy
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Alarcon, Emilio I.
    Univ Ottawa, Canada.
    Zakaria, Nadia
    Antwerp Univ Hosp, Belgium; Univ Antwerp, Belgium.
    Meek, Keith M.
    Cardiff Univ, Wales.
    Griffith, May
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Univ Montreal, Canada; Univ Montreal, Canada.
    Correction: Short peptide analogs as alternatives to collagen in pro-regenerative corneal implants (vol 69, pg 120, 2018)2018In: Acta Biomaterialia, ISSN 1742-7061, E-ISSN 1878-7568, Vol. 81, p. 330-331Article in journal (Other academic)
    Abstract [en]

    n/a

  • 7.
    Jangamreddy, Jaganmohan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. LV Prasad Eye Inst, India.
    Haagdorens, Michel K. C.
    Antwerp Univ Hosp, Belgium; Univ Antwerp, Belgium.
    Mirazul Islam, Mohammad Mirazul
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Lewis, Philip
    Cardiff Univ, Wales.
    Samanta, Ayan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Fagerholm, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
    Liszka, Aneta
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Kozak Ljunggren, Monika
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Buznyk, Oleksiy
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Alarcon, Emilio I.
    Univ Ottawa, Canada.
    Zakaria, Nadia
    Antwerp Univ Hosp, Belgium; Univ Antwerp, Belgium.
    Meek, Keith M.
    Cardiff Univ, Wales.
    Griffith, May
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Univ Montreal, Canada; Univ Montreal, Canada.
    Short peptide analogs as alternatives to collagen in pro-regenerative corneal implants2018In: Acta Biomaterialia, ISSN 1742-7061, E-ISSN 1878-7568, Vol. 69, p. 120-130Article in journal (Refereed)
    Abstract [en]

    Short collagen-like peptides (CLPs) are being proposed as alternatives to full-length collagen for use in tissue engineering, on their own as soft hydrogels, or conjugated to synthetic polymer for mechanical strength. However, despite intended clinical use, little is known about their safety and efficacy, mechanism of action or degree of similarity to the full-length counterparts they mimic. Here, we show the functional equivalence of a CLP conjugated to polyethylene glycol (CLP-PEG) to full-length recombinant human collagen in vitro and in promoting stable regeneration of corneal tissue and nerves in a pre- clinicalmini-pig model. We also show that these peptide analogs exerted their pro-regeneration effects through stimulating extracellular vesicle production by host cells. Our results support future use of CLP-PEG implants for corneal regeneration, suggesting the feasibility of these or similar peptide analogs in clinical application in the eye and other tissues. Statement of significance Although biomaterials comprising full-length recombinant human collagen and extracted animal collagen have been evaluated and used clinically, these macromolecules provide only a limited number of functional groups amenable to chemical modification or crosslinking and are demanding to process. Synthetic, customizable analogs that are functionally equivalent, and can be readily scaled-up are therefore very desirable for pre-clinical to clinical translation. Here, we demonstrate, using cornea regeneration as our test bed, that collagen-like-peptides conjugated to multifunctional polyethylene glycol (CLP-PEG) when grafted into mini-pigs as corneal implants were functionally equivalent to recombinant human collagen-based implants that were successfully tested in patients. We also show for the first time that these materials affected regeneration through stimulation of extracellular vesicle production by endogenous host cells that have migrated into the CLP-PEG scaffolds. (C) 2018 Acta Materialia Inc. Published by Elsevier Ltd.

  • 8.
    Jangamreddy, Jaganmohan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Haagdorens, Michel K. C.
    Antwerp Univ Hosp, Belgium; Univ Antwerp, Belgium.
    Mirazul Islam, Mohammad Mirazul
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Lewis, Philip
    Cardiff Univ, Wales.
    Samanta, Ayan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Fagerholm, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
    Liszka, Aneta
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Kozak Ljunggren, Monika
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Buznyk, Oleksiy
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Alarcon, Emilio I.
    Univ Ottawa Heart Inst, Canada.
    Zakaria, Nadia
    Antwerp Univ Hosp, Belgium; Univ Antwerp, Belgium.
    Meek, Keith M.
    Univ Ottawa Heart Inst, Canada.
    Griffith, May
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Univ Montreal, Canada; Univ Montreal, Canada.
    Short peptide analogs as alternatives to collagen in pro-regenerative corneal implants (vol 69, pg 120, 2018)2019In: Acta Biomaterialia, ISSN 1742-7061, E-ISSN 1878-7568, Vol. 88, p. 556-557Article in journal (Refereed)
    Abstract [en]

    n/a

  • 9.
    Jangamreddy, Jaganmohan Reddy
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Cancer and cancer stem cell targeting agents: A focus on salinomycin and apoptin2015Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Current cancer treatments involving surgery, radiotherapy, and chemotherapy target the vast majority of cancer cells, but they are only partially effective in eliminating the disease. Failure to eliminate cancer with conventional treatments can lead to recurrence, which usually kills patient. This often occurs when cancer cells develop resistance to cancer drugs or when cancer-initiating cells (cancer stem cells), unaffected by existing treatment procedures, are present. Here, we studied two drugs, salinomycin and apoptin, that exhibit great potential in the future of cancer treatment not only for restricting malignancy, but also in preventing tumor recurrence. Salinomycin is an antibiotic that was used in poultry farming that is now used clinically to target cancer stem cells, and apoptin is a chicken anemia virus-derived protein that is capable of detecting and killing transformed cells. In this study, we delved into the molecular mechanism of salinomycin action leading to cancer cell death. We showed that salinomycin induces autophagy in both cancer and normal primary cells. We further demonstrated that salinomycin promotes mitochondrial fission, thus increasing mitochondrial mass and mitochondria-specific autophagy, mitophagy. Salinomycin-induced cell death was both necrotic and apoptotic as determined by increased release of HMGB1 and caspase-3, -8 and -9 activation. We also found that stress responses of normal and cancer cells to salinomycin differ and this difference is aggravated by starvation conditions. We proposed that a combinational treatment with glucose starvation, or glucose analogues such as 2DG or 2FDG, might enhance the effects of salinomycin on cancer cells while protecting normal cells. We previously reported that apoptin interacts with BCRABL1, a protein that is expressed in patients with chronic myeloid leukemia (CML). We located a minimal region on the apoptin protein that triggers inhibition of downstream BCR-ABL1 signaling effects. This deca-peptide region was tested on patient samples and was shown to effectively kill cancer cells derived from patients, similar to the drug Imatinib. We further show that the apoptin decapeptide is cytotoxic to Imatinib-resistant patient-derived cancer cells. Thus, we identified a novel therapeutic targeting agent that can not only overcome drug resistance, but it can also induce cancer cell death without affecting normal cells.

    List of papers
    1. Salinomycin induces activation of autophagy, mitophagy and affects mitochondrial polarity: Differences between primary and cancer cells
    Open this publication in new window or tab >>Salinomycin induces activation of autophagy, mitophagy and affects mitochondrial polarity: Differences between primary and cancer cells
    Show others...
    2013 (English)In: Biochimica et Biophysica Acta. Molecular Cell Research, ISSN 0167-4889, E-ISSN 1879-2596, Vol. 1833, no 9, p. 2057-2069Article in journal (Refereed) Published
    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.

    Keywords
    cancer stem cells; mitofusin; mitophagy; mTOR; PGC1α; salinomycin
    National Category
    Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
    Identifiers
    urn:nbn:se:liu:diva-91756 (URN)10.1016/j.bbamcr.2013.04.011 (DOI)000321173900004 ()23639289 (PubMedID)
    Available from: 2013-05-01 Created: 2013-05-01 Last updated: 2017-12-06
    2. Monitoring of autophagy is complicated: Salinomycin as an example
    Open this publication in new window or tab >>Monitoring of autophagy is complicated: Salinomycin as an example
    2015 (English)In: Biochimica et Biophysica Acta. Molecular Cell Research, ISSN 0167-4889, E-ISSN 1879-2596, ISSN 0167-4889, Vol. 1853, no 3, p. 604-610Article in journal (Refereed) Published
    Abstract [en]

    Monitoring of autophagy is challenging because of its multiple steps and lack of single befitting technique for a complete mechanistic understanding, which makes the task complicated. Here, we evaluate the functionality of autophagy triggered by salinomycin (anti-cancer stem cell agent) using flow cytometry and advanced microscopy. We show that salinomycin does induce functional autophagy at lower concentrations and such a dose is cell type-dependent. For example, PC3 cells show active autophagic flux at 10μM concentration of salinomycin while murine embryonic fibroblasts already show an inhibition of flux at such doses. A higher concentration of salinomycin (i.e. 30μM) inhibits autophagic flux in both cell types. The data confirms our previous findings that salinomycin is an inducer of autophagy, whereas autophagic flux inhibition is a secondary response.

    Place, publisher, year, edition, pages
    Elsevier, 2015
    Keywords
    Autophagic flux; GFP-LC3; Salinomycin; Vacuolization; mTandem GFP-RFP LC3; p62/SQSTRM1
    National Category
    Basic Medicine Cell and Molecular Biology
    Identifiers
    urn:nbn:se:liu:diva-113565 (URN)10.1016/j.bbamcr.2014.12.022 (DOI)000349878500007 ()25541282 (PubMedID)
    Available from: 2015-01-23 Created: 2015-01-23 Last updated: 2018-01-11Bibliographically approved
    3. Glucose starvation-mediated inhibition of salinomycin induced autophagy amplifies cancer cell specific cell death
    Open this publication in new window or tab >>Glucose starvation-mediated inhibition of salinomycin induced autophagy amplifies cancer cell specific cell death
    Show others...
    2015 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 6, no 12, p. 10134-10145Article in journal (Refereed) Published
    Abstract [en]

    Salinomycin has been used as treatment for malignant tumors in a small number of humans, causing far less side effects than standard chemotherapy. Several studies show that Salinomycin targets cancer-initiating cells (cancer stem cells, or CSC) resistant to conventional therapies. Numerous studies show that Salinomycin not only reduces tumor volume, but also decreases tumor recurrence when used as an adjuvant to standard treatments. In this study we show that starvation triggered different stress responses in cancer cells and primary normal cells, which further improved the preferential targeting of cancer cells by Salinomycin. Our in vitro studies further demonstrate that the combined use of 2-Fluoro 2-deoxy D-glucose, or 2-deoxy D-glucose with Salinomycin is lethal in cancer cells while the use of Oxamate does not improve cell death-inducing properties of Salinomycin. Furthermore, we show that treatment of cancer cells with Salinomycin under starvation conditions not only increases the apoptotic caspase activity, but also diminishes the protective autophagy normally triggered by the treatment with Salinomycin alone. Thus, this study underlines the potential use of Salinomycin as a cancer treatment, possibly in combination with short-term starvation or starvation-mimicking pharmacologic intervention.

    Place, publisher, year, edition, pages
    IMPACT JOURNALS LLC, 2015
    Keywords
    Glucose starvation, 2DG, 2FDG, Normoxia and Hypoxia, Differential Stress Response, autophagy, Akt, Tricirabine, Salinomycin
    National Category
    Cell and Molecular Biology
    Identifiers
    urn:nbn:se:liu:diva-113707 (URN)000358874600039 ()
    Available from: 2015-01-29 Created: 2015-01-29 Last updated: 2018-01-11Bibliographically approved
    4. Mapping of Apoptin interaction with BCR-ABL1, and development of apoptin-based targeted therapy
    Open this publication in new window or tab >>Mapping of Apoptin interaction with BCR-ABL1, and development of apoptin-based targeted therapy
    Show others...
    2014 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 5, no 16, p. 7198-7211Article in journal (Refereed) Published
    Abstract [en]

    Majority of chronic myeloid leukemia patients experience an adequate therapeutic effect from imatinib however, 26-37% of patients discontinue imatinib therapy due to a suboptimal response or intolerance. Here we investigated derivatives of apoptin, a chicken anemia viral protein with selective toxicity towards cancer cells, which can be directed towards inhibiting multiple hyperactive kinases including BCR-ABL1. Our earlier studies revealed that a proline-rich segment of apoptin interacts with the SH3 domain of fusion protein BCR-ABL1 (p210) and acts as a negative regulator of BCR-ABL1 kinase and its downstream targets. In this study we show for the first time, the therapeutic potential of apoptin-derived decapeptide for the treatment of CML by establishing the minimal region of apoptin interaction domain with BCR-ABL1. We further show that the apoptin decapeptide is able to inhibit BCR-ABL1 down stream target c-Myc with a comparable efficacy to full-length apoptin and Imatinib. The synthetic apoptin is able to inhibit cell proliferation in murine (32Dp210), human cell line (K562), and ex vivo in both imatinib-resistant and imatinib sensitive CML patient samples. The apoptin based single or combination therapy may be an additional option in CML treatment and eventually be feasible as curative therapy.

    Keywords
    apoptin, BCR-ABL1, CML, imatinib, STAT5
    National Category
    Basic Medicine
    Identifiers
    urn:nbn:se:liu:diva-111667 (URN)000347920100055 ()25216532 (PubMedID)
    Available from: 2014-10-28 Created: 2014-10-28 Last updated: 2018-01-11Bibliographically approved
  • 10.
    Jangamreddy, Jaganmohan Reddy
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Jain, Mayur V.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Hallbeck, Anna-Lotta
    Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology. Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences.
    Roberg, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Otorhinolaryngology in Linköping.
    Lotfi, Kourosh
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pharmacology.
    Los, Marek Jan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Pomeranian Medical University, Szczecin, Poland.
    Glucose starvation-mediated inhibition of salinomycin induced autophagy amplifies cancer cell specific cell death2015In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 6, no 12, p. 10134-10145Article in journal (Refereed)
    Abstract [en]

    Salinomycin has been used as treatment for malignant tumors in a small number of humans, causing far less side effects than standard chemotherapy. Several studies show that Salinomycin targets cancer-initiating cells (cancer stem cells, or CSC) resistant to conventional therapies. Numerous studies show that Salinomycin not only reduces tumor volume, but also decreases tumor recurrence when used as an adjuvant to standard treatments. In this study we show that starvation triggered different stress responses in cancer cells and primary normal cells, which further improved the preferential targeting of cancer cells by Salinomycin. Our in vitro studies further demonstrate that the combined use of 2-Fluoro 2-deoxy D-glucose, or 2-deoxy D-glucose with Salinomycin is lethal in cancer cells while the use of Oxamate does not improve cell death-inducing properties of Salinomycin. Furthermore, we show that treatment of cancer cells with Salinomycin under starvation conditions not only increases the apoptotic caspase activity, but also diminishes the protective autophagy normally triggered by the treatment with Salinomycin alone. Thus, this study underlines the potential use of Salinomycin as a cancer treatment, possibly in combination with short-term starvation or starvation-mimicking pharmacologic intervention.

  • 11.
    Jangamreddy, Jaganmohan Reddy
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Los, Marek J
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Mitoptosis, a novel mitochondrial death mechanism leading predominantly to activation of autophagy2012In: Hepatitis Monthly, ISSN 1735-143X, E-ISSN 1735-3408, Vol. 12, no 8, p. e6159-Article in journal (Refereed)
  • 12.
    Jangamreddy, Jaganmohan Reddy
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Panigrahi, Soumya
    Case Western Reserve University, Cleveland, OH, USA.
    Lotfi, Kourosh
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pharmacology.
    Yadav, Manisha
    CSIR-Central Drug Research Institute, Lucknow, India.
    Maddika, Subbareddy
    Centre for DNA Fingerprinting and Diagnostics (CDFD), Hyderabad, India.
    Tripathi, Anil Kumar
    King George's Medical University, Lucknow, India.
    Sanyal, Sabyasachi
    CSIR-Central Drug Research Institute, Lucknow, India.
    Los, Marek Jan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Pomeranian Medical University, Szczecin, Poland.
    Mapping of Apoptin interaction with BCR-ABL1, and development of apoptin-based targeted therapy2014In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 5, no 16, p. 7198-7211Article in journal (Refereed)
    Abstract [en]

    Majority of chronic myeloid leukemia patients experience an adequate therapeutic effect from imatinib however, 26-37% of patients discontinue imatinib therapy due to a suboptimal response or intolerance. Here we investigated derivatives of apoptin, a chicken anemia viral protein with selective toxicity towards cancer cells, which can be directed towards inhibiting multiple hyperactive kinases including BCR-ABL1. Our earlier studies revealed that a proline-rich segment of apoptin interacts with the SH3 domain of fusion protein BCR-ABL1 (p210) and acts as a negative regulator of BCR-ABL1 kinase and its downstream targets. In this study we show for the first time, the therapeutic potential of apoptin-derived decapeptide for the treatment of CML by establishing the minimal region of apoptin interaction domain with BCR-ABL1. We further show that the apoptin decapeptide is able to inhibit BCR-ABL1 down stream target c-Myc with a comparable efficacy to full-length apoptin and Imatinib. The synthetic apoptin is able to inhibit cell proliferation in murine (32Dp210), human cell line (K562), and ex vivo in both imatinib-resistant and imatinib sensitive CML patient samples. The apoptin based single or combination therapy may be an additional option in CML treatment and eventually be feasible as curative therapy.

  • 13.
    Panigrahi, Soumya
    et al.
    Lerner Research Institute, Cleveland, Ohio, USA.
    Stetefeld, Joerg
    University of Manitoba, Winnipeg, Canada.
    Jangamreddy, Jaganmohan R.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Mandal, Soma
    University of Manitoba, Winnipeg, Canada.
    Mandal, Sanat K.
    Memorial University of Newfoundland, Canada.
    Los, Marek Jan
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Modeling of Molecular Interaction between Apoptin, BCR-Abl and CrkL - An Alternative Approach to Conventional Rational Drug Design2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 1, p. 6-20Article in journal (Refereed)
    Abstract [en]

    In this study we have calculated a 3D structure of apoptin and through modeling and docking approaches, we show its interaction with Bcr-Abl oncoprotein and its downstream signaling components, following which we confirm some of the newly-found interactions by biochemical methods. Bcr-Abl oncoprotein is aberrantly expressed in chronic myelogenous leukaemia (CIVIL). It has several distinct functional domains in addition to the Abl kinase domain. The SH3 and SH2 domains cooperatively play important roles in autoinhibiting its kinase activity. Adapter molecules such as Grb2 and CrkL interact with proline-rich region and activate multiple Bcr-Abl downstream signaling pathways that contribute to growth and survival. Therefore, the oncogenic effect of Bcr-Abl could be inhibited by the interaction of small molecules with these domains. Apoptin is a viral protein with well-documented cancer-selective cytotoxicity. Apoptin attributes such as SH2-like sequence similarity with CrkL SH2 domain, unique SH3 domain binding sequence, presence of proline-rich segments, and its nuclear affinity render the molecule capable of interaction with Bcr-Abl. Despite almost two decades of research, the mode of apoptins action remains elusive because 3D structure of apoptin is unavailable. We performed in silico three-dimensional modeling of apoptin, molecular docking experiments between apoptin model and the known structure of Bcr-Abl, and the 3D structures of SH2 domains of CrkL and Bcr-Abl. We also biochemically validated some of the interactions that were first predicted in silica. This structure-property relationship of apoptin may help in unlocking its cancer-selective toxic properties. Moreover, such models will guide us in developing of a new class of Potent apoptin-like molecules with greater selectivity and potency.

  • 14.
    Patra, Hirak Kumar
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Imani, Roghayeh
    Linköping University, Department of Physics, Chemistry and Biology, Biosensors and Bioelectronics. Linköping University, Faculty of Science & Engineering. Univ,of Ljubljana, Slovenia; University of Ljubljana, Slovenia.
    Jangamreddy, Jaganmohan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Pazoki, Meysam
    Uppsala University, Sweden.
    Iglic, Ales
    University of Ljubljana, Slovenia.
    Turner, Anthony
    Linköping University, Department of Physics, Chemistry and Biology, Biosensors and Bioelectronics. Linköping University, Faculty of Science & Engineering.
    Tiwari, Ashutosh
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, Faculty of Science & Engineering. Tekidag AB, SE-58330 Linkoping, Sweden.
    On/off-switchable anti-neoplastic nanoarchitecture2015In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, no 14571, p. 1-9Article in journal (Refereed)
    Abstract [en]

    Throughout the world, there are increasing demands for alternate approaches to advanced cancer therapeutics. Numerous potentially chemotherapeutic compounds are developed every year for clinical trial and some of them are considered as potential drug candidates. Nanotechnology-based approaches have accelerated the discovery process, but the key challenge still remains to develop therapeutically viable and physiologically safe materials suitable for cancer therapy. Here, we report a high turnover, on/off-switchable functionally popping reactive oxygen species (ROS) generator using a smart mesoporous titanium dioxide popcorn (TiO2 Pops) nanoarchitecture. The resulting TiO2 Pops, unlike TiO2 nanoparticles (TiO2 NPs), are exceptionally biocompatible with normal cells. Under identical conditions, TiO2 Pops show very high photocatalytic activity compared to TiO2 NPs. Upon on/off-switchable photo activation, the TiO2 Pops can trigger the generation of high-turnover flash ROS and can deliver their potential anticancer effect by enhancing the intracellular ROS level until it crosses the threshold to open the death gate, thus reducing the survival of cancer cells by at least six times in comparison with TiO2 NPs without affecting the normal cells.

  • 15.
    Reddy Jangamreddy, Jaganmohan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Panigrahi, Soumya
    Department of Medicine/Infectious Diseases, Case Western Reserve University, Cleveland, USA.
    Los, Marek J.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Pomeranian Medical University, Poland.
    Monitoring of autophagy is complicated: Salinomycin as an example2015In: Biochimica et Biophysica Acta. Molecular Cell Research, ISSN 0167-4889, E-ISSN 1879-2596, ISSN 0167-4889, Vol. 1853, no 3, p. 604-610Article in journal (Refereed)
    Abstract [en]

    Monitoring of autophagy is challenging because of its multiple steps and lack of single befitting technique for a complete mechanistic understanding, which makes the task complicated. Here, we evaluate the functionality of autophagy triggered by salinomycin (anti-cancer stem cell agent) using flow cytometry and advanced microscopy. We show that salinomycin does induce functional autophagy at lower concentrations and such a dose is cell type-dependent. For example, PC3 cells show active autophagic flux at 10μM concentration of salinomycin while murine embryonic fibroblasts already show an inhibition of flux at such doses. A higher concentration of salinomycin (i.e. 30μM) inhibits autophagic flux in both cell types. The data confirms our previous findings that salinomycin is an inducer of autophagy, whereas autophagic flux inhibition is a secondary response.

  • 16.
    Vilas Jain, Mayur
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Jangamreddy, Jaganmohan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Grabarek, Jerzy
    Pomeranian Medical University, Poland.
    Schweizer, Frank
    University of Manitoba, Canada.
    Klonisch, Thomas
    University of Manitoba, Canada.
    Cieslar-Pobuda, Artur
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Silesian Technical University, Poland.
    Los, Marek Jan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Pomeranian Medical University, Poland; Medical University of Silesia, Poland.
    Nuclear localized Akt enhances breast cancer stem-like cells through counter-regulation of p21(Waf1/Cip1) and p27(kip1)2015In: Cell Cycle, ISSN 1538-4101, E-ISSN 1551-4005, Vol. 14, no 13, p. 2109-2120Article in journal (Refereed)
    Abstract [en]

    Cancer stem-like cells (CSCs) are a rare subpopulation of cancer cells capable of propagating the disease and causing cancer recurrence. In this study, we found that the cellular localization of PKB/Akt kinase affects the maintenance of CSCs. When Akt tagged with nuclear localization signal (Akt-NLS) was overexpressed in SKBR3 and MDA-MB468 cells, these cells showed a 10-15% increase in the number of cells with CSCs enhanced ALDH activity and demonstrated a CD44(+High)/CD24(-Low) phenotype. This effect was completely reversed in the presence of Akt-specific inhibitor, triciribine. Furthermore, cells overexpressing Akt or Akt-NLS were less likely to be in G0/G1 phase of the cell cycle by inactivating p21(Waf1/Cip1) and exhibited increased clonogenicity and proliferation as assayed by colony-forming assay (mammosphere formation). Thus, our data emphasize the importance the intracellular localization of Akt has on stemness in human breast cancer cells. It also indicates a new robust way for improving the enrichment and culture of CSCs for experimental purposes. Hence, it allows for the development of simpler protocols to study stemness, clonogenic potency, and screening of new chemotherapeutic agents that preferentially target cancer stem cells. Summary: The presented data, (i) shows new, stemness-promoting role of nuclear Akt/PKB kinase, (ii) it underlines the effects of nuclear Akt on cell cycle regulation, and finally (iii) it suggests new ways to study cancer stem-like cells.

  • 17.
    Wark, Landon
    et al.
    University of Manitoba,Winnipeg, Canada.
    Novak, David
    University of Manitoba,Winnipeg, Canada.
    Sabbaghian, Nelly
    McGill University, Montreal, QC, Canada.
    Amrein, Lilian
    Segal Cancer Centre, Lady Davis Institute, Jewish General Hospital, Montreal, QC, Canada.
    Jangamreddy, Jaganmohan Reddy
    Lady Davis Institute, Jewish General Hospital, Montreal, QC, Canada.
    Cheang, Mary
    University of Manitoba,Winnipeg, Canada.
    Pouchet, Carly
    McGill University, Montreal, QC, Canada.
    Aloyz, Raquel
    McGill University, Montreal, QC, Canada.
    Foulkes, William D.
    McGill University, Montreal, QC, Canada.
    Mai, Sabine
    University of Manitoba,Winnipeg, Canada.
    Tischkowitz, Marc
    McGill University, Montreal, QC, Canada.
    Heterozygous mutations in the PALB2 hereditary breast cancer predisposition gene impact on the three-dimensional nuclear organization of patient-derived cell lines2013In: Genes, Chromosomes and Cancer, ISSN 1045-2257, E-ISSN 1098-2264, Vol. 52, no 5, p. 480-494Article in journal (Refereed)
    Abstract [en]

    PALB2/FANCN is a BRCA1- and BRCA2-interacting Fanconi Anemia (FA) protein crucial for key BRCA2 genome caretaker functions. Heterozygous germline mutations in PALB2 predispose to breast cancer and biallelic mutations cause FA. FA proteins play a critical role in the telomere maintenance pathway, with telomeric shortening observed in FA cells. Less is known about telomere maintenance in the heterozygous state. Here, we investigate the roles of PALB2 heterozygous mutations in genomic instability, an important carcinogenesis precursor. Patient-derived lymphoblastoid (LCL) and fibroblast (FCL) cell lines with monoallelic truncating PALB2 mutations were investigated using a combination of molecular imaging techniques including centromeric FISH, telomeric Q-FISH and spectral karyotyping (SKY). Mitomycin C and Cisplatin sensitivity was assayed via cellular metabolism of WST-1. The PALB2 c.229delT FCL showed increases in telomere counts associated with increased mean intensity compared with two wild-type FCLs generated from first-degree relatives (P =1.04E-10 and P =9.68E-15) and it showed evidence of chromosomal rearrangements. Significant differences in centromere distribution were observed in one of three PALB2 heterozygous FCLs analyzed when compared with PALB2 wild-type, BRCA1 and BRCA2 heterozygous FCLs. No significant consistently increased sensitivity to Mitomycin C or Cisplatin was observed in LCLs. Our results are suggestive of an altered centromere distribution profile and a telomere instability phenotype. Together, these may indicate critical nuclear organization defects associated with the predisposition to transformation and early stage development of PALB2-related cancers.

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