3 years ago

CDK6 protects epithelial ovarian cancer from platinum-induced death via FOXO3 regulation

CDK6 protects epithelial ovarian cancer from platinum-induced death via FOXO3 regulation
Joshua Armenia, Alessandra Dall'Acqua, Gennaro Chiappetta, Sara Benevol, Maura Sonego, Loredana Militello, Roberto Sorio, Ilenia Pellizzari, Marina Bagnoli, Giorgio Giorda, Vincenzo Canzonieri, Monica Schiappacassi, Delia Mezzanzanica, Daniela Califano, Gustavo Baldassarre, Barbara Belletti, Sara D'Andrea, Ilenia Pellarin
Epithelial ovarian cancer (EOC) is an infrequent but highly lethal disease, almost invariably treated with platinum-based therapies. Improving the response to platinum represents a great challenge, since it could significantly impact on patient survival. Here, we report that silencing or pharmacological inhibition of CDK6 increases EOC cell sensitivity to platinum. We observed that, upon platinum treatment, CDK6 phosphorylated and stabilized the transcription factor FOXO3, eventually inducing ATR transcription. Blockage of this pathway resulted in EOC cell death, due to altered DNA damage response accompanied by increased apoptosis. These observations were recapitulated in EOC cell lines in vitro, in xenografts in vivo, and in primary tumor cells derived from platinum-treated patients. Consistently, high CDK6 and FOXO3 expression levels in primary EOC predict poor patient survival. Our data suggest that CDK6 represents an actionable target that can be exploited to improve platinum efficacy in EOC patients. As CDK4/6 inhibitors are successfully used in cancer patients, our findings can be immediately transferred to the clinic to improve the outcome of EOC patients. In epithelial ovarian cancer cells, platinum favours binding and phosphorylation of FOXO3 by the CDK6/cyclin D3 complex. FOXO3 is thus stabilized and binds the ATR promoter thereby inducing its transcription and preventing platinum-induced cell death.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.15252/emmm.201607012

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