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Intrinsic differences in cisplatin sensitivity of head and neck cancer celllines correlates to lysosomal pH
Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Oto-Rhiono-Laryngology and Head & Neck Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Reconstruction Centre, Department of ENT - Head and Neck Surgery UHL.
Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden.
Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.ORCID iD: 0000-0003-4075-159X
2010 (English)In: Head and Neck, ISSN 1043-3074, E-ISSN 1097-0347, Vol. 32, no 9, 1185-1194 p.Article 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. Vol. 32, no 9, 1185-1194 p.
Keyword [en]
apoptosis, cathepsin, chemotherapy resistance, lysosome, V0V1-ATPase
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:liu:diva-15136DOI: 10.1002/hed.21317ISI: 000281528100008OAI: oai:DiVA.org:liu-15136DiVA: diva2:54564
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: 2017-12-07Bibliographically approved
In thesis
1. Impact of Lysosomal Function in Cancer and Apoptosis
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. 112 p.
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: 2017-08-30Bibliographically approved

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Nilsson, CathrineRoberg, KarinÖllinger, Karin

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Experimental PathologyFaculty of Health SciencesOto-Rhiono-Laryngology and Head & Neck SurgeryDepartment of ENT - Head and Neck Surgery UHLDepartment of Clinical Pathology and Clinical Genetics
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