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MLH1 expression sensitises ovarian cancer cells to cell death mediated by XIAP inhibition
1Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA.
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.
Insights
X-linked inhibitor of apoptosis protein (XIAP) and mismatch repair protein (MLH1) influence epithelial ovarian cancer (EOC) response to cisplatin. XIAP inhibitors may enhance EOC sensitivity to MLH1-dependent apoptosis.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- X-linked inhibitor of apoptosis protein (XIAP) regulates apoptosis by controlling caspase levels, impacting epithelial ovarian cancer (EOC) response to chemotherapy.
- Mismatch repair protein (MLH1) is implicated in cisplatin-induced apoptosis via p53-dependent and -independent pathways.
Purpose of the Study:
- To correlate MLH1 expression with clinical response and survival in advanced EOC patients treated with platinum drugs.
- To investigate if MLH1 loss determines anti-apoptotic responses to cisplatin mediated by XIAP in EOC cell lines with varying p53 status.
Main Methods:
- Correlation analysis of MLH1 expression with clinical outcomes in advanced EOC.
- Investigation of XIAP-mediated anti-apoptosis in EOC cell lines with differential p53 and MLH1 status.
- Assessment of cisplatin and 6-thioguanine sensitivity, MLH1 proteolysis, XIAP destabilization, and caspase-3 activity.
Main Results:
- MLH1-proficient cells showed higher cisplatin-induced cell killing compared to MLH1-defective cells.
- Wild-type MLH1 or its re-expression enhanced sensitivity to the MMR-dependent agent 6-thioguanine.
- Cisplatin and 6-thioguanine treatment led to MLH1 proteolysis, XIAP destabilization, and increased caspase-3 activity. XIAP inhibition enhanced MLH1 proteolysis and cell death in MLH1-proficient cells.
Conclusions:
- MLH1 status is a key determinant of EOC sensitivity to cisplatin.
- XIAP plays a crucial role in regulating MLH1 stability and apoptosis.
- XIAP inhibitors represent a potential strategy to sensitize EOC to MLH1-dependent apoptosis.
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