Format

Send to

Choose Destination
Oncotarget. 2016 Jun 21;7(25):38380-38391. doi: 10.18632/oncotarget.9526.

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

Wang X1,2,3, Zhang W1,3, Yan Z1,3,4, Liang Y1,3, Li L1,3, Yu X2,3, Feng Y2,3, Fu S2,3, Zhang Y5, Zhao H5, Yu J6, Jeong LS6, Guo X2,3, Jia L1,3.

Author information

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.

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).

KEYWORDS:

Cullin-RING ligases; MLN4924 (pevonedistat); neddylation; prostate cancer; radiotherapy

PMID:
27224919
PMCID:
PMC5122397
DOI:
10.18632/oncotarget.9526
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Impact Journals, LLC Icon for PubMed Central
Loading ...
Support Center