Inhibitor of apoptosis proteins and associated factors in pancreatic cancer.

摘要

Since the phenomenon was first identified, apoptosis has been proposed to serve as a barrier to the development of cancer in metazoans. Over the years, the inability to carry out apoptosis has been implicated in the initiation, formation and progression of tumors. Moreover, acquired resistance to apoptosis is now believed to represent a major obstacle to the successful application of oncotherapies. Caspases play a central role in the induction and execution of apoptosis. As such, their activity must be tightly regulated. To date, inhibitor of apoptosis proteins (IAPs) are the only known intrinsic regulators of caspase function. The present study focused on the identification of molecular targets differentially expressed in normal and cancer cells that could serve to facilitate the rational design of anti-cancer therapies. We hypothesized that variations in the levels of key apoptotic regulators such as caspases, IAPs and their antagonists could conceivably contribute to the acknowledged resistance of pancreatic cancer cells to cytotoxic therapies.; Our first specific aim was to derive an expression profile of apoptotic modulator/effector genes in pancreatic cancer cell lines. Our analysis uncovered a tendency towards up-regulation of IAP expression (namely cIAP-2) and down-regulation of pro-apoptotic factors such as caspases and the Xiap antagonist Xaf-1 in these cell lines. In particular, Xaf1 protein expression appeared to be completely repressed in neoplastic cell lines. Moreover, over-expression of one or more IAPs was observed in several solid malignancies. Lastly, while Xiap expression and subcellular localization were not altered in evolving intraductal lesions and pancreatic tumors, immunohistological surveys uncovered over-expression and nuclear redistribution of cIAP-1, cIAP-2 and survivin in pancreatic adenocarcinomas.; Our second objective was to determine if differential expression of IAPs influenced the sensitivity of three human pancreatic cancer cell lines to drug-induced apoptosis. In vitro studies uncovered a good correlation between transcriptional up-regulation of IAPs, caspase-dependent cleavage of Xiap, activation of downstream effector caspase-3 and rapidity of onset of etoposide-induced apoptosis in these cell lines. In particular, endogenous levels of cIAP-2 mRNA appeared to be good predictors of etoposide-responsiveness. However, attempts at sensitizing pancreatic cancer cells to etoposide by down-modulating Xiap expression via over-expression of Xaf-1 or siRNA-mediated degradation of Xiap were unsuccessful. (Abstract shortened by UMI.)