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Cyclin D1 silencing impairs DNA double strand break repair, sensitizes BRCA1 wildtype ovarian cancer cells to olaparib

  • Qian Zhong
    Correspondence
    Correspondence to: Q. Zhong, Department of Gynecology and Obstetrics, West China Second University Hospital of Sichuan University, Chengdu 610041, PR China.
    Affiliations
    Department of Gynecology and Obstetrics, West China Second University Hospital of Sichuan University, Chengdu, PR China

    Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu, PR China
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  • Zhongyi Hu
    Affiliations
    Center for Research on Reproduction & Women's Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
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  • Qiao Li
    Affiliations
    Physical Examination Center, West China Hospital, Sichuan University, Chengdu, PR China
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  • Tao Yi
    Affiliations
    Department of Gynecology and Obstetrics, West China Second University Hospital of Sichuan University, Chengdu, PR China

    Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu, PR China
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  • Jinke Li
    Affiliations
    Department of Gynecology and Obstetrics, West China Second University Hospital of Sichuan University, Chengdu, PR China

    Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu, PR China
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  • Hanshuo Yang
    Correspondence
    Correspondence to: H. Yang, State Key Laboratory of Biotherapy and Cancer Center of Sichuan University, Chengdu 610041, PR China.
    Affiliations
    State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, PR China
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Published:November 07, 2018DOI:https://doi.org/10.1016/j.ygyno.2018.10.027

      Highlights

      • Olaparib could reduce the expression level of cyclin D1 protein in ovarian cancer cells.
      • Silencing of cyclin D1 could sensitize BRCA1 wildtype ovarian cancer cells to olaparib in vitro and in vivo.
      • Silencing of cyclin D1 could mimic a BRCAness phenotype and induce G0/G1 cell cycle arrest in ovarian cancer cells.

      Abstract

      Objective

      Poly(ADP-ribose) polymerase inhibitors (PARPi) are active in cancer cells that have impaired repair of DNA by the homologous recombination (HR) pathway. Strategies that disrupt HR may sensitize HR-proficient tumors to PARP inhibition. As a component of the core cell cycle machinery, cyclin D1 has unexpected function in DNA repair, suggesting that targeting cyclin D1 may represent a plausible strategy for expanding the utility of PARPi in ovarian cancer.

      Methods

      BRCA1 wildtype ovarian cancer cells (A2780 and SKOV3) were treated with a combination of CCND1 siRNA and olaparib in vitro. Cell viability was assessed by MTT. The effects of the combined treatment on DNA damage repair and cell cycle progression were examined to dissect molecular mechanisms. In vivo studies were performed in an orthotopic ovarian cancer mouse model. Animals were treated with a combination of lentivirus-mediated CCND1 shRNA and olaparib or olaparib plus scrambled shRNA. Molecular downstream effects were examined by immunohistochemistry.

      Results

      Silencing of cyclin D1 sensitized ovarian cancer cells to olaparib through interfering with RAD51 accumulation and inducing cell cycle G0/G1 arrest. Treatment of lentivirus-mediated CCND1-shRNA in nude mice statistically significantly augmented the olaparib response (mean tumor weight ± SD, CCND1-shRNA plus olaparib vs scrambled shRNA plus olaparib: 0.172 ± 0.070 g vs 0.324 ± 0.044 g, P< 0.05).

      Conclusions

      Silencing of cyclin D1 combined with olaparib may lead to substantial benefit for ovarian cancer management by mimicking a BRCAness phenotype, and induction of G0/G1 cell cycle arrest.

      Keywords

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