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Nilsson, Cathrine
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Publications (8 of 8) Show all publications
Appelqvist, H., Nilsson, C., Garner, B., Brown, A. J., Kågedal, K. & Öllinger, K. (2011). Attenuation of the Lysosomal Death Pathway by Lysosomal Cholesterol Accumulation. American Journal of Pathology, 178(2), 629-639
Open this publication in new window or tab >>Attenuation of the Lysosomal Death Pathway by Lysosomal Cholesterol Accumulation
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2011 (English)In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 178, no 2, p. 629-639Article in journal (Refereed) Published
Abstract [en]

In the past decade, lysosomal membrane permeabilization (LMP) has emerged as a significant component of cell death signaling. The mechanisms by which lysosomal stability is regulated are not yet fully understood, but changes in the lysosomal membrane lipid composition have been suggested to be involved. Our aim was to investigate the importance of cholesterol in the regulation of lysosomal membrane permeability and its potential impact on apoptosis. Treatment of normal human fibroblasts with U18666A, an amphiphilic drug that inhibits cholesterol transport and causes accumulation of cholesterol in lysosomes, rescued cells from lysosome-dependent cell death induced by the lysosomotropic detergent 0-methyl-serine dodecylamide hydrochloride (MSDH), staurosporine (STS), or cisplatin. LMP was decreased by pretreating cells with U18666A, and there was a linear relationship between the cholesterol content of lysosomes and their resistance to permeabilization induced by MSDH. U18666A did not induce changes in expression or localization of 70-kDa heat shock proteins (Hsp70) or antiapoptotic Bcl-2 proteins known to protect the lysosomal membrane. Induction of autophagy also was excluded as a contributor to the protective mechanism. By using Chinese hamster ovary (CHO) cells with lysosomal cholesterol overload due to a mutation in the cholesterol transporting protein Niemann-Pick type C1 (NPC1), the relationship between lysosomal cholesterol accumulation and protection from lysosome-dependent cell death was confirmed. Cholesterol accumulation in lysosomes attenuates apoptosis by increasing lysosomal membrane stability.

Place, publisher, year, edition, pages
American Society for Investigative Pathology (ASIP), 2011
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-66151 (URN)10.1016/j.ajpath.2010.10.030 (DOI)000287264400018 ()
Available from: 2011-03-04 Created: 2011-03-04 Last updated: 2017-12-11Bibliographically approved
Nilsson, C., Roberg, K., Grafström, R. C. & Öllinger, K. (2010). Intrinsic differences in cisplatin sensitivity of head and neck cancer celllines correlates to lysosomal pH. Head and Neck, 32(9), 1185-1194
Open this publication in new window or tab >>Intrinsic differences in cisplatin sensitivity of head and neck cancer celllines correlates to lysosomal pH
2010 (English)In: Head and Neck, ISSN 1043-3074, E-ISSN 1097-0347, Vol. 32, no 9, p. 1185-1194Article in journal (Refereed) Published
Abstract [en]

Cisplatin is part of the treatment regime of head and neck squamous cell carcinomas (HNSCC). In order to predict the clinical outcome of the treatment, markers for evaluation of the intrinsic cisplatin sensitivity are inquired. In this study we characterize the lysosomal compartment and compare cisplatin sensitivity in five HNSCC lines and normal oral keratinocytes (NOKs). Cisplatin sensitivity differed 3-fold between the least and most sensitive cell lines, and the cisplatin LD50 correlated significantly to lysosomal pH, which varied from 4.3 in NOKs to 4.9 in the most resistant HNSCC line. Lysosomes are acidified by the V0V1-ATPase complex located in the lysosomal membrane. Interestingly, in cell lines exhibiting high lysosomal pH, we found decreased expression of the V0V1-ATPase B2 subunit, possibly explaining the defective acidification. In all cell lines, exposure to cisplatin caused activation of caspase-3. Cisplatin exposure was accompanied by lysosomal membrane permeabilization and inhibition of the llysosomal cathepsins B, D and L partly prevented cell death. No correlation between cisplatin sensitivity and expression of cathepsins B, D and L or secretion of their respective proforms into the culture medium was found in the cell lines studied. We conclude that lysosomal pH and expression of V0V1-ATPase subunits are possible future markers of intrinsic cisplatin sensitivity.

Place, publisher, year, edition, pages
John Wiley & Sons, 2010
Keywords
apoptosis, cathepsin, chemotherapy resistance, lysosome, V0V1-ATPase
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-15136 (URN)10.1002/hed.21317 (DOI)000281528100008 ()
Note

The previous status of this article was Manuscript and the working title was Radiation and cisplatin sensitivity in head and neck cancer cells with stem cell properties.

Available from: 2008-10-17 Created: 2008-10-17 Last updated: 2018-02-12Bibliographically approved
Johansson, A.-C., Appelqvist, H., Nilsson, C., Kågedal, K., Roberg, K. & Öllinger, K. (2010). Regulation of apoptosis-associated lysosomal membrane permeabilization. APOPTOSIS, 15(5), 527-540
Open this publication in new window or tab >>Regulation of apoptosis-associated lysosomal membrane permeabilization
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2010 (English)In: APOPTOSIS, ISSN 1360-8185, Vol. 15, no 5, p. 527-540Article in journal (Refereed) Published
Abstract [en]

Lysosomal membrane permeabilization (LMP) occurs in response to a large variety of cell death stimuli causing release of cathepsins from the lysosomal lumen into the cytosol where they participate in apoptosis signaling. In some settings, apoptosis induction is dependent on an early release of cathepsins, while under other circumstances LMP occurs late in the cell death process and contributes to amplification of the death signal. The mechanism underlying LMP is still incompletely understood; however, a growing body of evidence suggests that LMP may be governed by several distinct mechanisms that are likely engaged in a death stimulus- and cell-type-dependent fashion. In this review, factors contributing to permeabilization of the lysosomal membrane including reactive oxygen species, lysosomal membrane lipid composition, proteases, p53, and Bcl-2 family proteins, are described. Potential mechanisms to safeguard lysosomal integrity and confer resistance to lysosome-dependent cell death are also discussed.

Place, publisher, year, edition, pages
Springer Science Business Media, 2010
Keywords
Lysosome, Lysosomal release, Caspases, Calpains, Hsp, LAMP
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-55061 (URN)10.1007/s10495-009-0452-5 (DOI)000276489900001 ()
Note

The original publication is available at www.springerlink.com: Ann-Charlotte Johansson, Hanna Appelqvist, Cathrine Nilsson, Katarina Kågedal, Karin Roberg and Karin Öllinger, Regulation of apoptosis-associated lysosomal membrane permeabilization, 2010, APOPTOSIS, (15), 5, 527-540. http://dx.doi.org/10.1007/s10495-009-0452-5 Copyright: Springer Science Business Media http://www.springerlink.com/

Available from: 2010-04-28 Created: 2010-04-28 Last updated: 2017-08-30
Danielsson, O., Nilsson, C., Lindvall, B. & Ernerudh, J. (2009). Expression of apoptosis related proteins in normal and diseased muscle: A possible role for Bcl-2 in protection of striated muscle. NEUROMUSCULAR DISORDERS, 19(6), 412-417
Open this publication in new window or tab >>Expression of apoptosis related proteins in normal and diseased muscle: A possible role for Bcl-2 in protection of striated muscle
2009 (English)In: NEUROMUSCULAR DISORDERS, ISSN 0960-8966, Vol. 19, no 6, p. 412-417Article in journal (Refereed) Published
Abstract [en]

The unique absence of major histocompatibility complex class I antigen (MHC-I) expression in normal muscle is one possible mechanism protecting striated muscle. In order to define their possible involvement in protection of normal muscle. we investigated the expression of molecules involved in muscle fibre death and survival mechanisms (Bcl-2, Fas, Fas-ligand and TRAIL), focusing on disorders with possible involvement of cytotoxic T cells. We studied muscle biopsies from 20 healthy volunteers, from 10 patients affected by polymyositis and 10 by Duchenne muscular dystrophy. By using immunohistochemistry, Western blot and real-time PCR we detected a constitutional expression of Bcl-2 in healthy muscle, whereas the expression was weaker in disease processes. Fas-L and TRAIL were not detected in muscle fibres, and Fas only in muscle affected by disease. Our findings indicate that the major apoptotic protein Bcl-2 might have a hitherto unrecognized role in the protection of normal muscle.

Keywords
Inflammatory myopathy, Apoptosis, Bcl-2, TRAIL, Fas and Fas-L
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-19795 (URN)10.1016/j.nmd.2009.03.008 (DOI)
Available from: 2009-08-10 Created: 2009-08-10 Last updated: 2020-01-16
Johansson, A.-C., Mild, H., Johansson, U., Nilsson, C., Antonsson, B., Kågedal, K. & Öllinger, K. (2008). Cathepsin D-mediated processing of Bid at Phe24, Trp48, and Phe183. International Journal of Experimental Pathology
Open this publication in new window or tab >>Cathepsin D-mediated processing of Bid at Phe24, Trp48, and Phe183
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2008 (English)In: International Journal of Experimental PathologyArticle in journal (Refereed) Submitted
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-13202 (URN)
Available from: 2008-04-17 Created: 2008-04-17 Last updated: 2017-08-30
Nilsson, C. (2008). Impact of Lysosomal Function in Cancer and Apoptosis. (Doctoral dissertation). Linköping: Linköping University Electronic Press
Open this publication in new window or tab >>Impact of Lysosomal Function in Cancer and Apoptosis
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Lysosomes, the recycling units of the cell, participate in the signaling pathway to apoptosis, which has stimulated the search for anti-cancer drugs targeting the lysosomal compartment. Lysosomes are, however, often altered in cancer cells. The aim of this thesis was to investigate the involvement of lysosomes during apoptosis in normal and cancer cells. We developed and used flow cytometric methods to measure cytosolic and lysosomal pH in cells. The cytosolic pH of U937 cells decreased, in a caspase-independent way, by 1.4 pH-units during apoptosis. Concomitantly, the lysosomal pH increased from 4.3 to 5.2, suggesting that proton release from lysosomes might be responsible for cytosolic acidification. When studying the lysosomal pH of head and neck squamous cell carcinoma (HNSCC) cell lines and normal oral keratinocytes (NOKs), the pH was significantly increased in three of five HNSCC cell lines, as compared to NOKs. Moreover, high lysosomal pH correlated to low expression of the B subunit of the vacuolar V0/V1-ATPase, a necessary component of the proton pump responsible for lysosomal acidification, and to reduced intrinsic cisplatin sensitivity. Cisplatin-induced apoptosis was, at least partly, dependent on lysosomal cathepsins. When investigating the colony formation ability of the two HNSCC cell lines LK0412 and SqCC/Y1, both were found to give rise to holoclones, indicating the presence of cells with cancer stem cell properties. Holoclone cells from the LK0412 cell line were less sensitive to cisplatin compared to more differentiated paraclone cells. Moreover, we detected differences in intracellular localization of the lysosomal compartment and expression of cathepsins between holo- and paraclone cells.

This thesis shows that changes found in the lysosomal compartment of cancer cells, such as alteration of lysosomal pH, might influence the outcome of a drug treatment. In addition, differences in drug sensitivity between subpopulations of tumor cells may affect the outcome of an anticancer therapy.

Abstract [sv]

Programmerad celldöd eller apoptos är en viktig mekanism för att upprätthålla balans mellan kroppens celler. Vid exempelvis cancer fungerar inte styrningen av denna process, vilket leder till att för få celler dör och en tumör kan växa ohämmat. Denna avhandling fokuserar på lysosomen, en mycket sur organell i cellen som är ansvarig för nedbrytning av cellmaterial. Hos cancerceller är lysosomerna ofta förändrade. Vi har undersökt lysosomernas roll under apoptos hos normala celler och hos cancerceller. För att kunna undersöka pH-förändringar under apoptos har vi utvecklat metoder att mäta cytosoliskt och lysosomalt pH med hjälp av en teknik som kallas flödescytometri. I apoptotiska celler ser vi att det cytosoliska pH:t sjunker med 1.4 pH-enheter till pH 5.7 samtidigt som det lysosomala pH:t ökar från 4.3 till 5.5. Detta tyder på att läckage av vätejoner från lysosomerna kan orsaka en försurning av cytosolen under apoptos. Genom att studera normala orala keratinocyter och jämföra dessa mot fem olika cellinjer eeablerade från skivepitelcancer från munhåla har vi också funnit ett samband mellan det lysosomala pH:t och känsligheten för cellgiftet cisplatin. Cisplatinbehandling leder till apoptos hos alla celler men en högre dos krävs hos celler som har ett högt lysosomalt pH. Tumörer tros innehålla ett litet antal sk cancerstamceller, som har förmåga att kontinuerligt kopiera sig själva utan att åldras. Överlevnad av dessa celler tros vara orsaken till att en tumör återkommer efter en behandling. Vi visar i denna avhandling att cellinjer från skivepitelcancer innehåller celler som har cancerstamcellsegenskaper, och att dessa celler kan ha en lägre känslighet mot cisplatin jämfört med mer utvecklade cancerceller.

Lysosomerna utgör ett intressant framtida mål för nya cancerläkemedel. I denna avhandling visar vi att förändringar i det lysosomala systemet kan påverka effekten av ett läkemedel och att skillnader mellan olika sub-populationer av celler från samma tumör kan påverka resultatet av en behandling.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2008. p. 112
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1080
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:liu:diva-15138 (URN)978-91-7393-794-8 (ISBN)
Public defence
2008-10-24, Linden, Campus US, Linköpings universitet, Linköping, 09:00 (English)
Opponent
Supervisors
Available from: 2008-10-17 Created: 2008-10-17 Last updated: 2020-03-29Bibliographically approved
Nilsson, C., Johansson, U., Johansson, A.-C., Kågedal, K. & Öllinger, K. (2006). Cytosolic acidification and lysosomal alkalinization during TNF-α induced apoptosis in U937 cells. Apoptosis (London), 11(7), 1149-1159
Open this publication in new window or tab >>Cytosolic acidification and lysosomal alkalinization during TNF-α induced apoptosis in U937 cells
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2006 (English)In: Apoptosis (London), ISSN 1360-8185, E-ISSN 1573-675X, Vol. 11, no 7, p. 1149-1159Article in journal (Refereed) Published
Abstract [en]

Apoptosis is often associated with acidification of the cytosol and since loss of lysosomal proton gradient and release of lysosomal content are early events during apoptosis, we investigated if the lysosomal compartment could contribute to cytosolic acidification. After exposure of U937 cells to tumor necrosis factor-α, three populations; healthy, pre-apoptotic, and apoptotic cells, were identified by flow cytometry. These populations were investigated regarding intra-cellular pH and apoptosis-associated events. There was a drop in cytosolic pH from 7.2 ± 0.1 in healthy cells to 6.8 ± 0.1 in pre-apoptotic, caspase-negative cells. In apoptotic, caspase-positive cells, the pH was further decreased to 5.7 ± 0.04. The cytosolic acidification was not affected by addition of specific inhibitors towards caspases or the mitochondrial F0F1-ATPase. In parallel to the cytosolic acidification, a rise in lysosomal pH from 4.3 ± 0.3, in the healthy population, to 4.8 ± 0.3 and 5.5 ± 0.3 in the pre-apoptotic- and apoptotic populations, respectively, was detected. In addition, lysosomal membrane permeability increased as detected as release of cathepsin D from lysosomes to the cytosol in pre-apoptotic and apoptotic cells. We, thus, suggest that lysosomal proton release is the cause of the cytosolic acidification of U937 cells exposed to TNF-α.

Place, publisher, year, edition, pages
Springer Netherlands, 2006
Keywords
Apoptosis, Cathepsin, Cytosolic acidification, Lysosomal alkalinization, pH, TNF-α
National Category
Cell Biology
Identifiers
urn:nbn:se:liu:diva-15135 (URN)10.1007/s10495-006-7108-5 (DOI)
Available from: 2008-10-17 Created: 2008-10-17 Last updated: 2018-10-08Bibliographically approved
Nilsson, C., Kågedal, K., Johansson, U. & Öllinger, K. (2004). Analysis of cytosolic and lysosomal pH in apoptotic cells by flow cytometry. Methods in Cell Science, 25(3-4), 185-194
Open this publication in new window or tab >>Analysis of cytosolic and lysosomal pH in apoptotic cells by flow cytometry
2004 (English)In: Methods in Cell Science, ISSN 1381-5741, Vol. 25, no 3-4, p. 185-194Article in journal (Refereed) Published
Abstract [en]

Several reports indicate that the cytosol is acidified during apoptosis although the mechanism is not yet fully elucidated. The most acidic organelle found in the cell is the lysosome, raising the possibility that lysosomal proton release may contribute to the cytosolic acidification. We here describe methods for measurement of the cytosolic and lysosomal pH in U937 cells by a dual-emission ratiometric technique suitable for flow cytometry. Cytosolic pH was analysed in cells loaded with the fluorescent probe BCECF, while lysosomal pH was determined after endocytosis of FITC-dextran. Standard curves were obtained by incubating cells in buffers with different pH in the presence of the proton ionophore nigericin. Apoptosis was induced by exposure of cells to 10ng/ml TNF- for 4h, and apoptotic cells were identified using a fluorescent marker for active caspases. By gating of control and apoptotic cells, the cytosolic and lysosomal pH were calculated in each population. The cytosolic pH was found to decrease from 7.2 ± 0.1 to 5.8s±0.1 and the lysosomal increased from 4.3±0.4 to 5.2±0.3. These methods will be useful in future attempts to evaluate the involvement of lysosomes in the acidification of the cytosol during apoptosis.

Keywords
Apoptosis, Flow cytometry, Lysosomes, pH measurement
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-15134 (URN)10.1007/s11022-004-8228-3 (DOI)
Available from: 2008-10-17 Created: 2008-10-17 Last updated: 2018-01-12Bibliographically approved
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