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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 G{sub 2} 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. - Highlights: • MLN4924 inhibits protein neddylation and malignant phenotypes of RCC cells. • Neddylation inhibition by MLN4924 triggers G{sub 2} cell-cycle arrest. • MLN4924 induces NOXA-dependent apoptosis.

Authors:
 [1];  [2];  [1];  [2];  [2]; ; ; ; ; ;  [3]; ;  [4];  [3];  [2];  [1];  [2];  [2];  [1];  [2] more »;  [2] « less
  1. Department of Laboratory Medicine, Huadong Hospital Affiliated to Fudan University, Shanghai, 200040 (China)
  2. (China)
  3. Cancer Institute, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032 (China)
  4. College of Pharmacy, Seoul National University, Seoul (Korea, Republic of)
Publication Date:
OSTI Identifier:
22719058
Resource Type:
Journal Article
Journal Name:
Biochemical and Biophysical Research Communications
Additional Journal Information:
Journal Volume: 490; Journal Issue: 4; Other Information: Copyright (c) 2017 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0006-291X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; APOPTOSIS; CARCINOMAS; CELL CYCLE; CELL PROLIFERATION; DOSES; ENZYMES; INHIBITION; KIDNEYS; PHENOTYPE

Citation Formats

Wang, Jiyou, College of Life Science, Dezhou University, Dezhou, 253023, Wang, Shiwen, Shanghai Key Laboratory of Clinical Geriatric Medicine, Shanghai, 200040, Research Center on Aging and Medicine, Fudan University, Shanghai, 200040, Zhang, Wenjuan, Wang, Xiaofang, Liu, Xiaojun, Liu, Liang, Li, Lihui, Liang, Yupei, Yu, Jinha, Jeong, Lak Shin, Jia, Lijun, Cancer Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, Zhao, Hu, Shanghai Key Laboratory of Clinical Geriatric Medicine, Shanghai, 200040, Research Center on Aging and Medicine, Fudan University, Shanghai, 200040, Zhang, Yanmei, Shanghai Key Laboratory of Clinical Geriatric Medicine, Shanghai, 200040, and Research Center on Aging and Medicine, Fudan University, Shanghai, 200040. Targeting neddylation pathway with MLN4924 (Pevonedistat) induces NOXA-dependent apoptosis in renal cell carcinoma. United States: N. p., 2017. Web. doi:10.1016/J.BBRC.2017.06.179.
Wang, Jiyou, College of Life Science, Dezhou University, Dezhou, 253023, Wang, Shiwen, Shanghai Key Laboratory of Clinical Geriatric Medicine, Shanghai, 200040, Research Center on Aging and Medicine, Fudan University, Shanghai, 200040, Zhang, Wenjuan, Wang, Xiaofang, Liu, Xiaojun, Liu, Liang, Li, Lihui, Liang, Yupei, Yu, Jinha, Jeong, Lak Shin, Jia, Lijun, Cancer Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, Zhao, Hu, Shanghai Key Laboratory of Clinical Geriatric Medicine, Shanghai, 200040, Research Center on Aging and Medicine, Fudan University, Shanghai, 200040, Zhang, Yanmei, Shanghai Key Laboratory of Clinical Geriatric Medicine, Shanghai, 200040, & Research Center on Aging and Medicine, Fudan University, Shanghai, 200040. Targeting neddylation pathway with MLN4924 (Pevonedistat) induces NOXA-dependent apoptosis in renal cell carcinoma. United States. doi:10.1016/J.BBRC.2017.06.179.
Wang, Jiyou, College of Life Science, Dezhou University, Dezhou, 253023, Wang, Shiwen, Shanghai Key Laboratory of Clinical Geriatric Medicine, Shanghai, 200040, Research Center on Aging and Medicine, Fudan University, Shanghai, 200040, Zhang, Wenjuan, Wang, Xiaofang, Liu, Xiaojun, Liu, Liang, Li, Lihui, Liang, Yupei, Yu, Jinha, Jeong, Lak Shin, Jia, Lijun, Cancer Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, Zhao, Hu, Shanghai Key Laboratory of Clinical Geriatric Medicine, Shanghai, 200040, Research Center on Aging and Medicine, Fudan University, Shanghai, 200040, Zhang, Yanmei, Shanghai Key Laboratory of Clinical Geriatric Medicine, Shanghai, 200040, and Research Center on Aging and Medicine, Fudan University, Shanghai, 200040. Sat . "Targeting neddylation pathway with MLN4924 (Pevonedistat) induces NOXA-dependent apoptosis in renal cell carcinoma". United States. doi:10.1016/J.BBRC.2017.06.179.
@article{osti_22719058,
title = {Targeting neddylation pathway with MLN4924 (Pevonedistat) induces NOXA-dependent apoptosis in renal cell carcinoma},
author = {Wang, Jiyou and College of Life Science, Dezhou University, Dezhou, 253023 and Wang, Shiwen and Shanghai Key Laboratory of Clinical Geriatric Medicine, Shanghai, 200040 and Research Center on Aging and Medicine, Fudan University, Shanghai, 200040 and Zhang, Wenjuan and Wang, Xiaofang and Liu, Xiaojun and Liu, Liang and Li, Lihui and Liang, Yupei and Yu, Jinha and Jeong, Lak Shin and Jia, Lijun and Cancer Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032 and Zhao, Hu and Shanghai Key Laboratory of Clinical Geriatric Medicine, Shanghai, 200040 and Research Center on Aging and Medicine, Fudan University, Shanghai, 200040 and Zhang, Yanmei and Shanghai Key Laboratory of Clinical Geriatric Medicine, Shanghai, 200040 and Research Center on Aging and Medicine, Fudan University, Shanghai, 200040},
abstractNote = {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 G{sub 2} 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. - Highlights: • MLN4924 inhibits protein neddylation and malignant phenotypes of RCC cells. • Neddylation inhibition by MLN4924 triggers G{sub 2} cell-cycle arrest. • MLN4924 induces NOXA-dependent apoptosis.},
doi = {10.1016/J.BBRC.2017.06.179},
journal = {Biochemical and Biophysical Research Communications},
issn = {0006-291X},
number = 4,
volume = 490,
place = {United States},
year = {2017},
month = {9}
}