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

Oncogene volume 31, pages 2175–2186 (2012)Cite this article

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.

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Acknowledgements

This work was supported by grants from the Canadian Institutes of Health Research (MOP-15691), the World Class University (WCU) program (R31-10056) through the National Research Foundation of Korea, funded by the Ministry of Education, Science and Technology.

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Authors and Affiliations

  1. Departments of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada

    A Y Ali, M R Abedini & B K Tsang

  2. Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada

    A Y Ali, M R Abedini & B K Tsang

  3. Department of Physiology and Pharmacology, Birjand University of Medical Sciences, Birjand, Iran

    M R Abedini

  4. Department of Obstetrics and Gynaecology, University of Ottawa, Ottawa, Ontario, Canada

    B K Tsang

  5. Department of Agricultural Biotechnology, World Class University (WCU) Biomodulation Major, College of Agriculture and Life Sciences, Seoul National University, Seoul, Republic of Korea

    B K Tsang

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  1. A Y Ali
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Correspondence to B K Tsang.

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Ali, A., Abedini, M. & Tsang, B. The oncogenic phosphatase PPM1D confers cisplatin resistance in ovarian carcinoma cells by attenuating checkpoint kinase 1 and p53 activation. Oncogene 31, 2175–2186 (2012). https://doi.org/10.1038/onc.2011.399

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