title: 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.
  
  
  CONCLUSIONS
  These data suggest that XIAP inhibitors may prove to be an effective means of sensitising EOC to MLH1-dependent apoptosis.
authors: Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA.
authors: X
authors: X
authors: Ding
authors: A B
authors: AB
authors: Mohd
authors: Z
authors: Z
authors: Huang
authors: T
authors: T
authors: Baba
authors: M Q
authors: MQ
authors: Bernardini
authors: H K
authors: HK
authors: Lyerly
authors: A
authors: A
authors: Berchuck
authors: S K
authors: SK
authors: Murphy
authors: A B
authors: AB
authors: Buermeyer
authors: G R
authors: GR
authors: Devi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D005260:Female; D006801:Humans; D000070957:MutL Protein Homolog 1; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D051745:Protein Kinase C-delta / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D013866:Thioguanine / Q000494:pharmacology*; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000037:antagonists & inhibitors*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D012333:RNA, Messenger; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D051745:Protein Kinase C-delta; D000070957:MutL Protein Homolog 1; D013866:Thioguanine; D002945:Cisplatin