Targeting neddylation pathway with MLN4924 (Pevonedistat) induces NOXA-dependent apoptosis in renal cell carcinoma

Jiyou Wang; Shiwen Wang; Wenjuan Zhang; Xiaofang Wang; Xiaojun Liu; Liang Liu; Lihui Li; Yupei Liang; Jinha Yu; Lak Shin Jeong; Lijun Jia; Hu Zhao; Yanmei Zhang

doi:10.1016/j.bbrc.2017.06.179

Targeting neddylation pathway with MLN4924 (Pevonedistat) induces NOXA-dependent apoptosis in renal cell carcinoma

Jiyou Wang, Shiwen Wang, Wenjuan Zhang, Xiaofang Wang, Xiaojun Liu, Liang Liu, Lihui Li, Yupei Liang, Jinha Yu, Lak Shin Jeong, Lijun Jia, Hu Zhao, Yanmei Zhang

Department of Pharmaceutical Sciences

Research output: Contribution to journal › Article › peer-review

13 Scopus citations

Abstract

Inhibition of protein neddylation pathway has emerged an attractive anticancer strategy in preclinical studies by using Nedd8-activating enzyme (NAE) inhibitor MLN4924 (Pevonedistat). Previous studies have reported the antitumor activity of MLN4924 mediated by its efficacy on apoptosis, autophagy and senescence. However, whether MLN4924 has any effect on renal carcinoma cells (RCC) remains unexplored. Here we reported that MLN4924 specifically inhibited protein neddylation pathway, leading to statistically significantly suppress the proliferation, survival and migration of RCC cells by inducing G₂ cell-cycle arrest, followed by apoptosis in a MLN4924 dose-dependent manner. Further mechanistic study revealed that MLN4924-induced apoptosis was mediated by substantial up-regulation of pro-apoptotic NOXA. These findings highlighted the anticancer effects of the neddylation inhibitors (e.g. MLN4924) for the treatment of RCC.

Original language	English
Pages (from-to)	1183-1188
Number of pages	6
Journal	Biochemical and Biophysical Research Communications
Volume	490
Issue number	4
DOIs	https://doi.org/10.1016/j.bbrc.2017.06.179
State	Published - 2 Sep 2017

Bibliographical note

Funding Information:
This work was supported by the Chinese Minister of Science and Technology grant [grant numbers 2016YFA0501800], National Natural Science Foundation Grant of China [grant numbers: 81602072, 81625081, 81372196, 81572340, 81400893], the “Shuguang Program” supported by Shanghai Education Development Foundation [grant numbers: 14SG07], the “Shanghai Sailing Program” [grant numbers: 2017YF1405000], and Shanghai Municipal Commission of Health and Family Planning, Key developing disciplines [grant numbers: 2015ZB0501].

Publisher Copyright:
© 2017

Keywords

Apoptosis
MLN4924
Neddylation
Renal cell carcinoma

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@article{b8700d16d0b34478bb9fff3c9833c166,

title = "Targeting neddylation pathway with MLN4924 (Pevonedistat) induces NOXA-dependent apoptosis in renal cell carcinoma",

abstract = "Inhibition of protein neddylation pathway has emerged an attractive anticancer strategy in preclinical studies by using Nedd8-activating enzyme (NAE) inhibitor MLN4924 (Pevonedistat). Previous studies have reported the antitumor activity of MLN4924 mediated by its efficacy on apoptosis, autophagy and senescence. However, whether MLN4924 has any effect on renal carcinoma cells (RCC) remains unexplored. Here we reported that MLN4924 specifically inhibited protein neddylation pathway, leading to statistically significantly suppress the proliferation, survival and migration of RCC cells by inducing G2 cell-cycle arrest, followed by apoptosis in a MLN4924 dose-dependent manner. Further mechanistic study revealed that MLN4924-induced apoptosis was mediated by substantial up-regulation of pro-apoptotic NOXA. These findings highlighted the anticancer effects of the neddylation inhibitors (e.g. MLN4924) for the treatment of RCC.",

keywords = "Apoptosis, MLN4924, Neddylation, Renal cell carcinoma",

author = "Jiyou Wang and Shiwen Wang and Wenjuan Zhang and Xiaofang Wang and Xiaojun Liu and Liang Liu and Lihui Li and Yupei Liang and Jinha Yu and Jeong, {Lak Shin} and Lijun Jia and Hu Zhao and Yanmei Zhang",

note = "Funding Information: This work was supported by the Chinese Minister of Science and Technology grant [grant numbers 2016YFA0501800], National Natural Science Foundation Grant of China [grant numbers: 81602072, 81625081, 81372196, 81572340, 81400893], the “Shuguang Program” supported by Shanghai Education Development Foundation [grant numbers: 14SG07], the “Shanghai Sailing Program” [grant numbers: 2017YF1405000], and Shanghai Municipal Commission of Health and Family Planning, Key developing disciplines [grant numbers: 2015ZB0501]. Publisher Copyright: {\textcopyright} 2017",

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AU - Wang, Jiyou

AU - Wang, Shiwen

AU - Zhang, Wenjuan

AU - Wang, Xiaofang

AU - Liu, Xiaojun

AU - Liu, Liang

AU - Li, Lihui

AU - Liang, Yupei

AU - Yu, Jinha

AU - Jeong, Lak Shin

AU - Jia, Lijun

AU - Zhao, Hu

AU - Zhang, Yanmei

N1 - Funding Information: This work was supported by the Chinese Minister of Science and Technology grant [grant numbers 2016YFA0501800], National Natural Science Foundation Grant of China [grant numbers: 81602072, 81625081, 81372196, 81572340, 81400893], the “Shuguang Program” supported by Shanghai Education Development Foundation [grant numbers: 14SG07], the “Shanghai Sailing Program” [grant numbers: 2017YF1405000], and Shanghai Municipal Commission of Health and Family Planning, Key developing disciplines [grant numbers: 2015ZB0501]. Publisher Copyright: © 2017

PY - 2017/9/2

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N2 - Inhibition of protein neddylation pathway has emerged an attractive anticancer strategy in preclinical studies by using Nedd8-activating enzyme (NAE) inhibitor MLN4924 (Pevonedistat). Previous studies have reported the antitumor activity of MLN4924 mediated by its efficacy on apoptosis, autophagy and senescence. However, whether MLN4924 has any effect on renal carcinoma cells (RCC) remains unexplored. Here we reported that MLN4924 specifically inhibited protein neddylation pathway, leading to statistically significantly suppress the proliferation, survival and migration of RCC cells by inducing G2 cell-cycle arrest, followed by apoptosis in a MLN4924 dose-dependent manner. Further mechanistic study revealed that MLN4924-induced apoptosis was mediated by substantial up-regulation of pro-apoptotic NOXA. These findings highlighted the anticancer effects of the neddylation inhibitors (e.g. MLN4924) for the treatment of RCC.

AB - Inhibition of protein neddylation pathway has emerged an attractive anticancer strategy in preclinical studies by using Nedd8-activating enzyme (NAE) inhibitor MLN4924 (Pevonedistat). Previous studies have reported the antitumor activity of MLN4924 mediated by its efficacy on apoptosis, autophagy and senescence. However, whether MLN4924 has any effect on renal carcinoma cells (RCC) remains unexplored. Here we reported that MLN4924 specifically inhibited protein neddylation pathway, leading to statistically significantly suppress the proliferation, survival and migration of RCC cells by inducing G2 cell-cycle arrest, followed by apoptosis in a MLN4924 dose-dependent manner. Further mechanistic study revealed that MLN4924-induced apoptosis was mediated by substantial up-regulation of pro-apoptotic NOXA. These findings highlighted the anticancer effects of the neddylation inhibitors (e.g. MLN4924) for the treatment of RCC.

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KW - Neddylation

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Targeting neddylation pathway with MLN4924 (Pevonedistat) induces NOXA-dependent apoptosis in renal cell carcinoma

Abstract

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Keywords

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