title: The oncogenic phosphatase PPM1D confers cisplatin resistance in ovarian carcinoma cells by attenuating checkpoint kinase 1 and p53 activation.
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. A determinant of CDDP sensitivity in OVCA, p53, is activated by checkpoint kinase 1 (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 has a role in CDDP resistance is unknown. Here, using pair-matched wild-type 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-Chk1 content between sensitive and resistant cells in response to CDDP; (ii) PPM1D, but not phosphoinositide-3-kinase-related kinase Ataxia Telangiectasia and Rad3 related protein (ATR), is important in the regulation of CDDP-induced Chk1 activation and OVCA cell chemosensitivity; (iii) PPM1D downregulation sensitizes resistant cells to CDDP primarily by activating Chk1 and p53. Our findings establish for the first time that PPM1D confers CDDP resistance in OVCA 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 OVCA.
authors.affiliation: Departments of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: A Y
authors.initials: AY
authors.lastname: Ali
authors.forename: M R
authors.initials: MR
authors.lastname: Abedini
authors.forename: B K
authors.initials: BK
authors.lastname: Tsang
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1; D002945:Cisplatin / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000502:physiology*; D011494:Protein Kinases / Q000235:genetics*; D000071636:Protein Phosphatase 2C; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; D016159:Tumor Suppressor Protein p53; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C000607458:PPM1D protein, human; D010749:Phosphoprotein Phosphatases; D000071636:Protein Phosphatase 2C; D002945:Cisplatin