A1-IRIS Overexpression Promotes Cisplatin

Downlo sion of apoptosis plays a key role in cancer development, drug resistance, and recurrence. The locus product protein BRCA1-IRIS is overexpressed in several cisplatin-resistant ovarian cancer cell but its relationship to resistance is uncertain. Here, we show that in human ovarian surface epitheOSE) cells, overexpression of BRCA1-IRIS triggers expression of the antiapoptotic protein survivin. ve modulation of phosphatidylinositol 3-kinase (PI3K) signaling or AKT silencing reduced survivin sion in this setting. Conversely, silencing BRCA1-IRIS in ovarian cancer cell lines derepressed PTEN sion along with the antiapoptotic AKT targets FOXO1 and FOXO3a, suppressing survivin expression. tin (≤50 μmol/L) exposure was sufficient to activate expression of the BRCA1-IRIS-AKT-survivin casn HOSE cells, whereas under similar conditions cisplatin failed to induce apoptosis in ovarian cancer es expressing this regulatory cascade. Mechanistic investigations indicated that BRCA1-IRIS triggers in expression through a PI3K/AKT-dependent pathway involving NF-κB, but also through a PI3K/ ndependent pathway involving PTEN, FOXO1, and FOXO3a. Our findings indicate how BRCA1-IRIS pression prevents chemotherapy-induced cell death by upregulating expression of survivin, and they overex highlight this regulatory cascade as a candidate focus to improve treatment of advanced drug-resistant ovarian cancers. Cancer Res; 70(21); OF1–10. ©2010 AACR.