miR-181 regulation of BAX controls cisplatin sensitivity of prostate cancer cells

Prostate cancer is one of the most common male malignancies and remains the second leading cause for cancer-specific mortalities in men. Cisplatin is commonly used as a chemotherapeutic agent against advanced cancers, and is now used in metastatic prostate cancers. Cisplatin exerts its cytotoxic effects by cross-linking genomic DNA (gDNA) which induces DNA damage on rapidly dividing cancer cells. However, cisplatin leads to systemic side effects and some patients never respond. Our previous report demonstrated an oncogenic role of miR-181a in human prostate cancer. In this study, we investigate the mechanistic potential of miR-181a in regulating cisplatin sensitivity in this context. We report that cisplatin treatment significantly enhanced miR-181a expression and that exogenous overexpression of miR-181a decreased sensitivity of prostate cancer cells to cisplatin. Additionally, we observed that cisplatin-resistant prostate cancer cells harbored high levels of miR-181a expression. Mechanistically, we demonstrate the pro-apoptotic protein, BAX, is typically enhanced by cisplatin treatment but its suppression promoted resistance. Here we demonstrate miR-181a regulation of BAX was mediated through a complimentary interaction with the 3'UTR of the BAX transcript. We subsequently show that BAX expression restored cisplatin sensitivity in miR-181a overexpressing prostate cancer cells. In parallel, we demonstrate inhibition of miR-181a restored BAX expression as well as cisplatin sensitivity in resistant cells. This study suggests that miR-181a is a potential therapeutic target for prostate cancers that are resistant to cisplatin.