Qian Zhong1, Zhongyi Hu2, Qiao Li3, Tao Yi4, Jinke Li4, Hanshuo Yang5. 1. 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. Electronic address: cdcd91761@163.com. 2. Center for Research on Reproduction & Women's Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. 3. Physical Examination Center, West China Hospital, Sichuan University, Chengdu, PR China. 4. 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. 5. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, PR China. Electronic address: yhansh@126.com.
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.
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 cancermouse 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.