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Acquisition of Cisplatin-resistance in Malignant Mesothelioma Cells Abrogates Na,K(+),2Cl(-;)-cotransport Activity and Cisplatin-induced Early Membrane Blebbing.
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry. Klinisk kemi.
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
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2008 (English)In: Cell Physiol Biochem, ISSN 1421-9778, Vol. 22, no 1-4, 45-56 p.Article in journal (Refereed) Published
Abstract [en]


Resistance mechanisms are important limiting factors in the treatment of solid malignancies with cis-diamminedichloroplatinum(II) (cisplatin). To gain further understanding of the effects of acquired cisplatin-resistance, we compared a human malignant pleural mesothelioma cell line (p31) to a sub-line (p31res1.2) with acquired cisplatin-resistance.


The role of Na(+),K(+),2Cl(-)-cotransport (NKCC1) activity in cisplatin-induced morphological changes and acquired cisplatin-resistance was investigated in a time-resolved manner. Acquisition of cisplatin-resistance resulted in markedly reduced NKCC1 activity, absence of cisplatin-induced early membrane blebbing, and increased basal caspase-3 activity. At equitoxic cisplatin concentrations, P31res1.2 cells had a faster activation of caspase-3 than P31 cells, but the end-stage cytotoxicity and number of cells with DNA fragmentation was similar. Bumetanide inhibition of NKCC1 activity in P31 cells repressed cisplatin-induced early-phase membrane blebbing but did not increase P31 cell resistance to cisplatin.


Together, these results suggest that active NKCC1 was necessary for cisplatin-induced early membrane blebbing of P31 cells, but not for cisplatin-resistance. Thus, acquisition of cisplatin-resistance can affect mechanisms that have profound effects on cisplatin-induced morphological changes but are not necessary for the subsequent progression to apoptosis.

Place, publisher, year, edition, pages
2008. Vol. 22, no 1-4, 45-56 p.
Keyword [en]
Apoptosis, Caspase-3, Cisplatin, Malignant mesothelioma, Membrane blebbing, Na+, K+, 2Cl--cotransport
URN: urn:nbn:se:umu:diva-10418DOI: doi:10.1159/000149782PubMedID: 18769031OAI: diva2:150089
Available from: 2008-09-08 Created: 2008-09-08 Last updated: 2011-08-25Bibliographically approved
In thesis
1. Cisplatin-resistance and cell death in malignant pleural mesothelioma cells
Open this publication in new window or tab >>Cisplatin-resistance and cell death in malignant pleural mesothelioma cells
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Malignant pleural mesothelioma (MPM) is an aggressive, treatment-resistant tumour. Cisplatin (cis-diamminedichloroplatinum (II)) is the best single-agent chemotherapy for MPM, but platinum-based combination therapies give the best overall response rates. However, cisplatin use is limited by resistance and severe side effects. This thesis has increased the knowledge concerning cisplatin-induced cell death in MPM by describing a novel potential therapeutic target, and three novel phenotypes of cisplatin-resistance in a human MPM cell line (P31) and its cisplatin-resistant sub-line (P31res1.2).

The novel potential therapeutic target, and one of the novel phenotypes, was cisplatin-resistant pro-apoptotic BH3-only proteins. In the P31 cells, cisplatin transiently increased pro-apoptotic BH3-only proteins during 6 h of exposure. This response was almost completely abrogated in the P31res1.2 cells. De-regulated caspase activity and activation was the second novel phenotype identified. The P31res1.2 cells had earlier, possibly mitochondria-independent, caspase-3 activation, increased basal caspase-3 activity and increased basal cleavage of caspase-8 and -9. Despite these differences, 6-h equitoxic cisplatin exposures rendered 50-60% of the cells apoptotic in both cell lines. The third novel phenotype was abrogated Na+K+2Cl--cotransporter (NKCC1) activity. Although NKCC1 activity was dispensable for cisplatin-induced apoptosis, balanced potassium transport activity was essential for P31 cell survival. Finally, the survival signalling protein Protein Kinase B (PKB or Akt) isoforms α and γ were constitutively activated in a PI3K-independent manner in P31 cells. In the P31res1.2 cells, PKBα and γ activities were increased, and there was PI3K-dependent activation of PKBβ. However, this increase in PKB isoform activity was not strongly associated to the cisplatin-resistance of the P31res1.2 cells.

Place, publisher, year, edition, pages
Umeå: Medicinsk biovetenskap, 2008. 104 p.
Umeå University medical dissertations, ISSN 0346-6612 ; 1192
apoptosis, BH3-only proteins, caspase, cell morphology, potassium transport, protein kinase B (PKB/Akt), signalling pathways, time
National Category
Other Clinical Medicine
urn:nbn:se:umu:diva-1680 (URN)978-91-7264-560-8 (ISBN)
Public defence
2008-08-29, E04, 6E, Norrlands Universitetssjukhus, Umeå, 09:00 (English)
Available from: 2008-05-28 Created: 2008-05-28 Last updated: 2010-01-18Bibliographically approved

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