title: Mechanisms of cisplatin-induced cell death in malignant mesothelioma cells: role of inhibitor of apoptosis proteins (IAPs) and caspases.
abstract: Malignant mesothelioma (MM) is an aggressive and highly chemoresistant tumour.             Although cisplatin is used in frontline therapy of this disease treatment remains             palliative at best. The biochemical pathways activated by cisplatin and the mechanisms             of resistance in mesothelioma cells are poorly understood. Overexpression of inhibitor             of apoptosis proteins (IAPs) has been described in clinical mesothelioma tumours             and proposed as therapeutic targets. In this study, we examined cisplatin-induced             cell death pathways and IAPs in three mesothelioma-derived cell lines. Cisplatin             induced cell death in mesothelioma cell lines was characterised by biochemical             mechanisms classically associated with apoptosis including: mitochondrial depolarisation,             phosphatidylserine translocation and caspase activation. Surprisingly mRNA expression             of IAPs in mesothelioma was not upregulated relative to primary mesothelial cells             except for survivin which was higher in the most resistant cell line. In contrast,             protein expression of both XIAP and survivin was upregulated in all mesothelioma             cells, consistent with post-translational regulation. Knockdown of either XIAP             or survivin by RNAi did not affect the sensitivity to cisplatin in any of the             cell lines. Survivin RNAi did, however, inhibit proliferation in the highest expressing             cell line, ONE58. The pan-caspase inhibitor z-VAD and the more selective caspase             3/7 inhibitor z-DEVD had no effect upon the sensitivity of any of the cell lines             to cisplatin indicating that caspase-independent pathways predominate. The findings             of the present study provide insights into cisplatin-induced mechanisms in mesothelioma             cells and show that alternative pathways are operating which may provide new options             for targeting this extremely resistant tumour.
authors.affiliation: School of Anatomy and Human Biology, The University of Western                     Australia, Crawley, WA, Australia.
authors.forename: Inez L
authors.initials: IL
authors.lastname: Cregan
authors.forename: Arun M
authors.initials: AM
authors.lastname: Dharmarajan
authors.forename: Simon A
authors.initials: SA
authors.lastname: Fox
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000096:biosynthesis / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000096:biosynthesis* / Q000235:genetics; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D053078:Membrane Potential, Mitochondrial; D008654:Mesothelioma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D000086002:Mesothelioma, Malignant; D010997:Pleural Neoplasms / Q000235:genetics / Q000378:metabolism
chemical_list: D051034:Inhibitor of Apoptosis Proteins; D020169:Caspases; D002945:Cisplatin