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.