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.

Acquired resistance of pancreatic cancer cells to cisplatin is multifactorial with cell context-dependent involvement of resistance genes

“…50, 51, 52, 53 Upregulation of these cisplatin resistance genes in AsPC1 cells relative to BxPC3 cells was also found in the GSE22973 data set (Gene Expression Omnibus; www.ncbi.nlm.nih.gov/geo), which supports the validity of our gene expression data (Supplementary Material, Supplementary Figure S7). …”

“…36 Oncoprotein c-MYC has been recently shown to promote cisplatin resistance through increased activity of PARP1, a key component of base excision repair. 50 Activated EGFR/RAS/MAPK signaling reportedly enhances cisplatin resistance by increased GSH levels and upregulation of transcriptional targets of AP1 complex, including GST2 gene. 21 …”

Assessment of cisplatin concentration and depth of penetration in human lung tissue after hyperthermic exposure†

“…In addition, another study characterized the cisplatin chemosensitivity of malignant mesothelioma cell lines and the dose-dependent cisplatin-induced cell death associated with apoptosis. The percentage of viable mesothelioma cells was approximately 60-80% at a cisplatin concentration of 1 µg/ml [24]. In both of the experimental investigations, the concentrations of cisplatin, which caused significant reductions in the viable mesothelioma cells, were nearly comparable with the concentrations of cisplatin measured in our samples of human lung tissue.…”

Photodynamic apoptosis and antioxidant activities of Brassica napus extracts in U937 and SK-HEP-1 cells

“…Reduced caspase activity at 100 lg/ml BNCE concentration was maybe due to cellular damage or caspase inactivation because of high BNCE concentration. These results are consistent with several reports that caspase-3/7 activation occurs later with lower doses of cisplatin, whereas caspase-3/7 activation occurs earlier and decreases as time passes with higher doses of cisplatin [21]. Caspase activity in SK-HEP-1 cells increased in a dose-dependent manner and reached a maximum at 100 lg/ml of BNCE.…”