PACT cessation overcomes ovarian cancer cell chemoresistance to cisplatin by enhancing p53-mediated apoptotic pathway

摘要

Ovarian cancer ranks as a lethal gynecological malignancy, and development of resistance to chemotherapy agents constitutes a major clinical challenge in ovarian carcinoma management. P53-associated cellular protein-testes derived (PACT) is recently proven to be expressed aberrantly in several cancers, and exerts a critical roles in cell proliferation, apoptosis and migration. Up to now, its function in chemoresistance of ovarian cancer remains poorly defined. In the present study, elevated expression of PACT was detected in cisplatin-resistant A2780/CP cells relative to cisplatin-sensitive A2780 cells. Moreover, exposure to cisplatin also increased PACT expression in A2780 cells. Functional assay confirmed that knockdown of PACT further aggravated the inhibitory effects of cisplatin on A2780 cell viability and enhanced cell apoptosis and caspase-3 activity in cisplatin-treated A2780 cells, indicating that PACT cessation elevates cell sensitivity to cisplatin in A2780 cells. Whilst, deletion of PACT affords little effects on cisplatin resistance in p53-defective SKOV3 cells. Mechanistic analysis corroborated that depression of PACT notably enhanced cisplatin-induced p53 expression, concomitant with the increases in p53-downstream Bax, p21 expression and decrease in Bcl-2 expression. Intriguingly, blocking the p53 pathway notably reversed PACT inhibition-increased cell sensitivity to cisplatin in A2780 cells by elevating cell viability and depressing cell apoptosis. Additionally, abrogation of p53 signaling also blunts PACT suppression-overcomed chemotherapy resistance to cisplatin in A2780/CP cells. Together, these findings confirm that targeting PACT may antagonize ovarian cancer cell resistance to cisplatin, supporting a promising therapeutic strategy to overcome the chemotherapy resistance in the treatment of ovarian cancer. (C) 2019 Published by Elsevier Inc.