MLN4924 (Pevonedistat), a protein neddylation inhibitor, suppresses proliferation and migration of human clear cell renal cell carcinoma

Shuai Tong,Wenguo Jiang,Hefen Yu,Yang Si,Lingqiang Zhang,Ping Xie

doi:10.1038/s41598-017-06098-y

Abstract

Neddylation is a post-translational protein modification associated with cancer development. MLN4924 is a neddylation inhibitor currently under investigation in multiple phase I studies on various malignancies, and its clincal name is Pevonedistat. It has been documented that MLN4924 blocks Cullins neddylation and inactivates CRLs and, in turn, triggers cell-cycle arrest, apoptosis, senescence and autophagy in many cancer cells. In this study, we investigated the anti-tumor effect of MLN4924 in human clear cell renal carcinoma (ccRCC). Levels of both Nedd8 activating enzyme E1 and Nedd8-conjugating enzyme E2 were higher in ccRCC tissues and RCC cancer cells than in normal. Moreover, MLN4924 treatment led to rapid inhibition of Cullin1 neddylation and notably suppressed growth and survival as well as migration in a dose-and time-dependent manner. Mechanistic studies revealed that MLN4924 induced the accumulation of a number of CRL substrates, including p21, p27 and Wee1 to trigger DNA damage and induce growth arrest at the G2/M phase. MLN4924 also induced anti-migration and anti-invasion by activating E-cadherin and repressing Vimentin. Taken together, this study provides the first evidence that neddylation pathway is overactive in ccRCC and that MLN4924 induces dose-dependent anti-proliferation, anti-migration, anti-invasion in ccRCC cells. The study thus indicates that MLN4924 has potential therapeutic value for the clinical treatment of renal cancer.

Highlights

Kidney cancer is one of the most common human malignancies neoplasms, and more than 300,000 new patients are diagnosed worldwide each year[1]
Cullin neddylation leads to activation of Cullin-RING ligases (CRLs), the largest family of E3 ubiquitin ligases, which are responsible for ubiquitylation and degradation of many key signaling or regulatory proteins[8]
What’s more, we found that MLN4924 blocked migration of renal cancer cells through upregulating E-cadherin and repressing of Vimentin

Summary

Introduction

Kidney cancer is one of the most common human malignancies neoplasms, and more than 300,000 new patients are diagnosed worldwide each year[1]. MLN4924 efficiently blocks neddylation of all Cullins, leading to accumulation of their substrates[18,19,20], which in turn triggers DNA replication stress, DNA damage response, cell-cycle arrest, apoptosis, autophagy, and senescence, collectively suppressing the growth of cancer cells[21,22,23,24]. Our data showed that MLN4924 markedly inhibited the growth of renal cancer cells by blocking Cullin[1] neddylation and subsequent accumulation their substrates. This led to a DNA damage response, G2-M cell cycle phase arrest and apoptosis. The study provides proof-of-concept evidence for the clinical investigation of this first-in-class anticancer agent in the treatment of renal cancers

Methods

Results

Conclusion