MLN4924 (Pevonedistat), a protein neddylation inhibitor, suppresses proliferation and migration of human clear cell renal cell carcinoma
2017
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 antimigration
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
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