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Molecular Medicine

, Volume 17, Issue 11–12, pp 1262–1274 | Cite as

The p53 Upregulated Modulator of Apoptosis (PUMA) Chemosensitizes Intrinsically Resistant Ovarian Cancer Cells to Cisplatin by Lowering the Threshold Set by Bcl-xL and Mcl-1

  • Zhu Yuan
  • Kang Cao
  • Chao Lin
  • Lei Li
  • Huan-yi Liu
  • Xin-yu Zhao
  • Lei Liu
  • Hong-xin Deng
  • Jiong Li
  • Chun-lai Nie
  • Yu-quan Wei
Research Article

Abstract

Ovarian cancer is the number one cause of death from gynecologic malignancy. A defective p53 pathway is a hallmark of ovarian carcinoma. The p53 mutation correlates significantly with resistance to platinum-based chemotherapy, early relapse and shortened overall survival in ovarian cancer patients. PUMA (p53 upregulated modulator of apoptosis), a BH3-only Bcl-2 family protein, was recently identified as a transcriptional target of p53 and a potent apoptosis inducer in various cancer cells. In this study, we showed that the induction of PUMA by cisplatin was abolished in p53-deficient SKOV3 cells. Elevated expression of PUMA-induced apoptosis and sensitized A2780s and SKOV3 ovarian cancer cells to cisplatin, and the combination of PUMA and low-dose cisplatin, significantly suppressed xenograft tumor growth in vivo through enhanced induction of apoptosis compared with treatment with PUMA or cisplatin alone. The effects of PUMA were mediated by enhanced caspase activation and release of cytochrome c and Smac (second mitochondria-derived activator of caspase) into the cytosol. Furthermore, PUMA chemosensitized intrinsically resistant SKOV3 cells to cisplatin through downregulation of B-cell lymphoma-extra large (Bcl-xL) and myeloid cell leukemia sequence 1 (Mcl-1). PUMA-mediated Bcl-xL downregulation mainly happened at the transcription level, whereas PUMA-induced Mcl-1 downregulation was associated with caspase-dependent cleavage and proteasome-mediated degradation. To our knowledge, these data suggest a new mechanism by which overexpression of PUMA enhances sensitivity of SKOV3 cells to cisplatin by lowering the threshold set simultaneously by Bcl-xL and Mcl-1. Taken together, our findings indicate that PUMA is an important modulator of therapeutic responses of ovarian cancer cells and is potentially useful as a chemosensitizer in ovarian cancer therapy.

Notes

Acknowledgments

The authors thank Dr. Bing Kan and Yong-qiu Mao for their technical support. This work was supported by the National Key Basic Research Program of China (2010CB529900) and Natural Science Foundation of China (30900744; 81071817/H1609).

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Copyright information

© The Feinstein Institute for Medical Research 2011

Authors and Affiliations

  • Zhu Yuan
    • 1
  • Kang Cao
    • 2
  • Chao Lin
    • 1
  • Lei Li
    • 1
  • Huan-yi Liu
    • 3
  • Xin-yu Zhao
    • 1
  • Lei Liu
    • 1
  • Hong-xin Deng
    • 1
  • Jiong Li
    • 1
  • Chun-lai Nie
    • 1
  • Yu-quan Wei
    • 1
  1. 1.State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical SchoolSichuan UniversityChengduChina
  2. 2.Department of Pathogen BiologyChengdu Medical CollegeChengduChina
  3. 3.Cancer CenterChengdu Military General HospitalChengduChina

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