Radiosensitization by the investigational NEDD8-activating enzyme inhibitor MLN4924 (pevonedistat) in hormone-resistant prostate cancer cells
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Xiaofang Wang1,2,3, Wenjuan Zhang1,3, Zi Yan1,3,4, Yupei Liang1,3, Lihui Li1,3, Xiaoli Yu2,3, Yan Feng2,3, Shen Fu2,3, Yanmei Zhang5, Hu Zhao5, Jinha Yu6, Lak Shin Jeong6, Xiaomao Guo2,3, Lijun Jia1,3
1Cancer Institute, Fudan University Shanghai Cancer Center, Collaborative Innovation Center of Cancer Medicine, Shanghai, 200032, China
2Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
3Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
4Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China
5Department of Clinical Laboratory, Huadong Hospital, Shanghai Key Laboratory of Clinical Geriatric Medicine, Research Center on Aging and Medicine, Fudan University, Shanghai, 200040, China
6College of Pharmacy, Seoul National University, Seoul, 151–742, Republic of Korea
Lak Shin Jeong, email: [email protected]
Xiaomao Guo, email: [email protected]
Lijun Jia, email: [email protected]
Keywords: neddylation, MLN4924 (pevonedistat), Cullin-RING ligases, prostate cancer, radiotherapy
Received: October 12, 2015 Accepted: May 01, 2016 Published: May 20, 2016
Salvage radiotherapy (SRT) is the first-line treatment for prostate cancer patients with biochemical recurrence following radical prostatectomy, and new specific radiosensitizers are in urgent need to enhance SRT effect. MLN4924 (also known as Pevonedistat), a specific inhibitor of NEDD8-activating enzyme, has recently entered phase I/II clinical trials in several malignancies. By inhibiting cullin neddylation, MLN4924 inactivates Cullin-RING ligases (CRL), which have been validated as an attractive radiosensitizing target. In our study, we demonstrate that MLN4924 can be used as a potent radiosensitizer in hormone-resistant prostate cancer cells. We found that MLN4924 inhibited cullin neddylation and sensitized prostate cancer cells to irradiation (IR). Mechanistically, MLN4924 enhanced IR-induced G2 cell-cycle arrest, by inducing accumulation of WEE1/p21/p27, three well-known CRL substrates. Importantly, siRNA knockdown of WEE1/p21/p27 partially abrogated MLN4924-induced G2 cell-cycle arrest, indicating a causal role of WEE1/p21/p27 in MLN4924-induced radiosensitization. Further mechanistic studies revealed that induction of DNA damage and apoptosis also contributed to MLN4924 radiosensitization in hormone-resistant prostate cancer cells. Our findings lay the foundation for future application of MLN4924 as a potential radiosensitizer in hormone refractory prostate cancer (HRPC).
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