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

Xiaofang Wang, Wenjuan Zhang, Zi Yan, Yupei Liang, Lihui Li, Xiaoli Yu, Yan Feng, Shen Fu, Yanmei Zhang, Hu Zhao, Jinha Yu, Lak Shin Jeong, Xiaomao Guo, Lijun Jia

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

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).

Original languageEnglish
Pages (from-to)38380-38391
Number of pages12
JournalOncotarget
Volume7
Issue number25
DOIs
StatePublished - 2016

Keywords

  • Cullin-RING ligases
  • MLN4924 (pevonedistat)
  • Neddylation
  • Prostate cancer
  • Radiotherapy

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