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).
Highlights
Prostate cancer is the most common form of cancer among males worldwide [1, 2]
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
Salvage radiotherapy (SRT) is recognized as the sole approach affording an opportunity of a cure to patients with localized prostate cancer who develop prostate-specific antigen (PSA) recurrence after radical prostatectomy and years of castration treatment [13]
Summary
Radical prostatectomy is one of the principal treatment modalities for localized prostate cancer [3]. Surgery provides excellent control rates, about 20%–40% patients will experience biochemical recurrence within 5 years, presenting with increasing serum prostate-specific antigen (PSA) levels, without any evidence of clinical failure [4,5,6,7,8,9]. In patients exhibiting PSA recurrence, SRT is considered to be the only curative treatment. With years of medical www.impactjournals.com/oncotarget or surgical castration treatment, the relapse cells are always characterized by hormone-resistance. In order to improve survival benefit of SRT, efficient radiosensitizing agents against hormone-resistant prostate cancer cells are urgent to be identified
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