MLH1 expression sensitises ovarian cancer cells to cell death mediated by XIAP inhibition

Abstract

BACKGROUND: The X-linked inhibitor of apoptosis protein (XIAP), an endogenous apoptosis suppressor, can determine the level of caspase accumulation and the resultant response to apoptosis-inducing agents such as cisplatin in epithelial ovarian cancer (EOC). In addition, the mismatch repair protein, hMLH1, has been linked to DNA damage-induced apoptosis by cisplatin by both p53-dependent and -independent mechanisms. METHODS: In this study, hMLH1 expression was correlated with clinical response to platinum drugs and survival in advanced stage (III -IV) EOC patients. We then investigated whether MLH1 loss was a determinant in anti-apoptosis response to cisplatin mediated by XIAP in isogenic and established EOC cell lines with differential p53 status. RESULTS: The percentage of cells undergoing cisplatin-induced cell killing was higher in MLH1-proficient cells than in MLH1-defective cells. In addition, the presence of wild-type hMLH1 or hMLH1 re-expression significantly increased sensitivity to 6-thioguanine, a MMR-dependent agent. Cell-death response to 6-thioguanine and cisplatin was associated with significant proteolysis of MLH1, with XIAP destabilisation and increased caspase-3 activity. The siRNA-mediated inhibition of XIAP increased MLH1 proteolysis and cell death in MLH1-proficient cells but not in MLH1-defective cells. CONCLUSION: These data suggest that XIAP inhibitors may prove to be an effective means of sensitising EOC to MLH1-dependent apoptosis.

HtrA1 sensitizes ovarian cancer cells to cisplatin‐induced cytotoxicity by targeting XIAP for degradation

“…By directly inhibiting the initiation and execution phases of the caspase cascade, XIAP protects cell from death in response to various cellular assaults 8. In ovarian cancer, expression of XIAP has been recognized as an important cell survivor factor that endows cell resistance to cisplatin‐induced apoptosis 9–12. On the basis of these facts, we hypothesized that HtrA1 may sensitize cell to chemotherapy through degrading XIAP.…”

Identification of key genes associated with the effect of estrogen on ovarian cancer using microarray analysis

“…The expression of MLH1 was sensitized to the cell death mediated by the inhibition of X-linked inhibitor of apoptosis protein in epithelial ovarian cancer [23]. Women with a mutation of MMR genes, including MLH1, MSH2 or MSH6, had 4-12 % risk of ovarian cancer [24].…”

Non-Steroidal Anti-Inflammatory Drugs, DNA Repair and Cancer

“…Decreased expression of hMLH1 can alter hPMS2 stability and consequently, genetic integrity. Moreover, hMLH1 and hPMS2 can have a role in activating cell-cycle checkpoints and promoting apoptosis (Cejka et al, 2003;Davis et al, 1998;Ding et al, 2009;McDaid et al, 2009;Sansom et al, 2003;Yanamadala & Ljungman, 2003;Zhang et al, 1999). Thus, a functional DNA mismatch repair system prohibits expansion of cells containing DNA damage (Carethers et al, 1996;Papouli et al, 2004).…”