Abstract 4884: The oncogenic phosphatase PPM1D confers cisplatin resistance in ovarian carcinoma cells by attenuating checkpoint kinase 1 and p53 activation

Abstract

Abstract Cisplatin (CDDP: cis-diamminedichloroplatinum) resistance is a major hurdle in the treatment of human ovarian cancer (OVCA). A better understanding of the mechanisms of CDDP resistance can greatly improve therapeutic outcome for patients. p53, a determinant of CDDP sensitivity in ovarian cancer, is activated by Chk1 in response to DNA damage. Although the oncogenic phosphatase Protein Phosphatase Magnesium-dependent 1 (PPM1D) can deactivate both p53 and Chk1 through site-specific dephosphorylation, whether PPM1D plays a role in CDDP resistance is unknown. Here, using pair-matched wt-p53 CDDP-sensitive (OV2008) and -resistant (C13*) cells, and p53-compromised CDDP-resistant cells (A2780cp, OCC-1, OVCAR-3, and SKOV3), we have demonstrated (i) the existence of site-specific differences in phospho-Ser-Checkpoint kinase 1 (Chk1) content between sensitive and resistant cells in response to CDDP; (ii) PPM1D, but not phosphoinositide-3-kinase-related kinase (ATR), is important in the regulation of CDDP-induced Chk1 activation and ovarian cancer cell chemosensitivity; (iii) PPM1D down-regulation sensitizes resistant cells to CDDP primarily by activating Chk1 and p53. Our findings establish for the first time that PPM1D confers CDDP resistance in ovarian cancer cells through attenuating CDDP-induced, Chk1-mediated, p53-dependent apoptosis. These findings extend the current knowledge on the molecular and cellular basis of cisplatin resistance and offer the rationale for PPMID as a potential target for treatment of chemoresistant ovarian cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4884. doi:1538-7445.AM2012-4884