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Preclinical Studies and Early Drug Development: In Vitro and In Vivo Assays and Models

Acquired-cisplatin resistance by BRCA1-IRIS over-expression in human ovarian epithelial cells

Dana-Farber Cancer Institute, Boston, MA

Abstract

B6

Evasion of apoptotic cell death plays a key role in cancer development, drug resistance and recurrence. BRCA1-IRIS, a product of BRCA1-locus alternative splicing, is over-expressed in multiple ovarian cancer cell lines. Its endogenous over-expression in ovarian cancer cell lines or ectopic overproduction in human ovarian surface epithelial cell lines induces the expression of two, known anti-apoptotic genes, AKT and survivin. Survivin too is over-expressed in ovarian cancer cell lines, in part through an AKT-driven mechanism. Survivin blocks apoptosis through inhibition of caspases. In this report, the role of BRCA1-IRIS in survivin/survival induction in ovarian cells is evaluated. Over-expression of BRCA1-IRIS induces AKT1/2 (not 3) over-expression/activation and thus survivin over-expression/activation. However, in the presence of high levels of BRCA1-IRIS, negative modulation of PI3`K (using pharmacological inhibitor, LY294002), or AKT (using siRNA or DN-AKT) only partially decreased survivin expression, suggesting that BRCA1-IRIS over-expression activates survivin up-regulation also by a PI3`K/AKT-independent mechanism. Interestingly, the cascade BRCA1-IRIS-> and/or AKT->survivin could be activated in ovarian cells by cisplatin treatment in a cell cycle-independent manner. This cascade inhibited cisplatin-induced apoptosis, whereas pre-treatment with siIRIS sensitized cells to it. We identified BRCA1-IRIS as an anti-apoptotic protein in ovarian cells and demonstrate that treatment with DNA damaging agent cisplatin activates the BRCA1-IRIS/AKT/survivin pathway that in part protects cells from drug-induced apoptosis.