Radiosensitization by the investigational NEDD8-activating enzyme inhibitor MLN4924 (pevonedistat) in hormone-resistant prostate cancer cells

Abstract

// Xiaofang Wang 1, 2, 3 , Wenjuan Zhang 1, 3 , Zi Yan 1, 3, 4 , Yupei Liang 1, 3 , Lihui Li 1, 3 , Xiaoli Yu 2, 3 , Yan Feng 2, 3 , Shen Fu 2, 3 , Yanmei Zhang 5 , Hu Zhao 5 , Jinha Yu 6 , Lak Shin Jeong 6 , Xiaomao Guo 2, 3 , Lijun Jia 1, 3 1 Cancer Institute, Fudan University Shanghai Cancer Center, Collaborative Innovation Center of Cancer Medicine, Shanghai, 200032, China 2 Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China 3 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China 4 Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China 5 Department of Clinical Laboratory, Huadong Hospital, Shanghai Key Laboratory of Clinical Geriatric Medicine, Research Center on Aging and Medicine, Fudan University, Shanghai, 200040, China 6 College of Pharmacy, Seoul National University, Seoul, 151–742, Republic of Korea Correspondence to: Lak Shin Jeong, email: lakjeong@snu.ac.kr Xiaomao Guo, email: guoxm1800@126.com Lijun Jia, email: ljjia@fudan.edu.cn Keywords: neddylation, MLN4924 (pevonedistat), Cullin-RING ligases, prostate cancer, radiotherapy Received: October 12, 2015      Accepted: May 01, 2016      Published: May 20, 2016 ABSTRACT 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).