Publications [#178156] of Gayathri R Devi

Papers Published

1. X Ding, AB Mohd, Z Huang, T Baba, MQ Bernardini, HK Lyerly, A Berchuck, SK Murphy, AB Buermeyer, GR Devi, MLH1 expression sensitises ovarian cancer cells to cell death mediated by XIAP inhibition., British journal of cancer, vol. 101 no. 2 (July, 2009), pp. 269-77, ISSN 1532-1827 [doi]
   (last updated on 2013/05/16)

   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. CONCLUSIONS: These data suggest that XIAP inhibitors may prove to be an effective means of sensitising EOC to MLH1-dependent apoptosis.

   Keywords:
   Adaptor Proteins, Signal Transducing • Apoptosis • Cell Line, Tumor • Cisplatin • Female • Humans • Nuclear Proteins • Ovarian Neoplasms • Protein Kinase C-delta • RNA, Messenger • Thioguanine • X-Linked Inhibitor of Apoptosis Protein • antagonists & inhibitors* • biosynthesis • biosynthesis* • drug effects • drug therapy* • genetics • metabolism • metabolism* • pharmacology* • physiology