title: Radiosensitization by the investigational NEDD8-activating enzyme inhibitor MLN4924 (pevonedistat) in hormone-resistant prostate cancer cells.
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).
authors.affiliation: Cancer Institute, Fudan University Shanghai Cancer Center, Collaborative Innovation Center of Cancer Medicine, Shanghai, 200032, China.|Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.|Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
authors.forename: Xiaofang
authors.initials: X
authors.lastname: Wang
authors.affiliation: Cancer Institute, Fudan University Shanghai Cancer Center, Collaborative Innovation Center of Cancer Medicine, Shanghai, 200032, China.|Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Cancer Institute, Fudan University Shanghai Cancer Center, Collaborative Innovation Center of Cancer Medicine, Shanghai, 200032, China.|Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.|Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China.
authors.forename: Zi
authors.initials: Z
authors.lastname: Yan
authors.affiliation: Cancer Institute, Fudan University Shanghai Cancer Center, Collaborative Innovation Center of Cancer Medicine, Shanghai, 200032, China.|Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
authors.forename: Yupei
authors.initials: Y
authors.lastname: Liang
authors.affiliation: Cancer Institute, Fudan University Shanghai Cancer Center, Collaborative Innovation Center of Cancer Medicine, Shanghai, 200032, China.|Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
authors.forename: Lihui
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.|Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Yu
authors.affiliation: Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.|Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Feng
authors.affiliation: Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.|Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
authors.forename: Shen
authors.initials: S
authors.lastname: Fu
authors.affiliation: Department of Clinical Laboratory, Huadong Hospital, Shanghai Key Laboratory of Clinical Geriatric Medicine, Research Center on Aging and Medicine, Fudan University, Shanghai, 200040, China.
authors.forename: Yanmei
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Clinical Laboratory, Huadong Hospital, Shanghai Key Laboratory of Clinical Geriatric Medicine, Research Center on Aging and Medicine, Fudan University, Shanghai, 200040, China.
authors.forename: Hu
authors.initials: H
authors.lastname: Zhao
authors.affiliation: College of Pharmacy, Seoul National University, Seoul, 151-742, Republic of Korea.
authors.forename: Jinha
authors.initials: J
authors.lastname: Yu
authors.affiliation: College of Pharmacy, Seoul National University, Seoul, 151-742, Republic of Korea.
authors.forename: Lak Shin
authors.initials: LS
authors.lastname: Jeong
authors.affiliation: Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.|Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
authors.forename: Xiaomao
authors.initials: X
authors.lastname: Guo
authors.affiliation: Cancer Institute, Fudan University Shanghai Cancer Center, Collaborative Innovation Center of Cancer Medicine, Shanghai, 200032, China.|Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
authors.forename: Lijun
authors.initials: L
authors.lastname: Jia
mesh_terms: D045744:Cell Line, Tumor; D003517:Cyclopentanes / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008297:Male; D000075687:NEDD8 Protein / Q000037:antagonists & inhibitors; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000201:enzymology / Q000532:radiotherapy*; D011743:Pyrimidines / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*
chemical_list: D003517:Cyclopentanes; D004791:Enzyme Inhibitors; D000075687:NEDD8 Protein; C082860:NEDD8 protein, human; D011743:Pyrimidines; D011838:Radiation-Sensitizing Agents; C539933:pevonedistat
keywords: Cullin-RING ligases; MLN4924 (pevonedistat); neddylation; prostate cancer; radiotherapy