Cisplatin-resistance and cell death in malignant pleural mesothelioma cells
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
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
Other Clinical Medicine
IdentifiersURN: urn:nbn:se:umu:diva-1680ISBN: 978-91-7264-560-8OAI: oai:DiVA.org:umu-1680DiVA: diva2:141815
2008-08-29, E04, 6E, Norrlands Universitetssjukhus, Umeå, 09:00 (English)
Zhivotovsky, Boris, Professor
Grankvist, Kjell, ProfessorHenriksson, Roger, ProfessorBehnam-Motlagh, Parviz, PhDJohansson, Anders, OD
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