Targeting Protein Neddylation to Inactivate Cullin-RING Ligases by Gossypol: A Lucky Hit or a New Start?

doi:10.2147/DDDT.S286373

	Targeting Protein Neddylation to Inactivate Cullin-RING Ligases by Gossypol: A Lucky Hit or a New Start?
	Yu, Qing 1,2,3,4; Sun, Yi 1,4
刊名	DRUG DESIGN DEVELOPMENT AND THERAPY
	2021
卷号	15
关键词	anti-cancer drug cullin-RING E3 ligases natural product high-throughput screen neddylation small-molecule inhibitors
ISSN号	1177-8881
DOI	10.2147/DDDT.S286373
通讯作者	Sun, Yi(yisun@zju.edu.cn)
英文摘要	Cullin-RING E3 ligases (CRLs) are the largest family of E3 ubiquitin ligases, responsible for about 20% of the protein degradation by the ubiquitin-proteasome system (UPS). Given their vital roles in multiple cellular processes, and over-activation in many human cancers, CRLs are validated as promising targets for anti-cancer therapies. Activation of CRLs requires cullin neddylation, a process catalysed by three neddylation enzymes. Recently, our group established an AlphaScreen-based in vitro cullin neddylation assay and employed it for high-throughput screening to search for small-molecule inhibitors targeting cullin neddylation. During our pilot screen, gossypol, a natural product extracted from cottonseeds, was identified as one of the most potent neddylation inhibitors of cullin-1 and cullin-5. We further demonstrated that gossypol blocks cullin neddylation by binding to cullin-1/-5 to inactivate CRL1/5 ligase activity, leading to accumulation of MCL-1 and NOXA, the substrates of CRL1 and CRL5, respectively. The combination of gossypol and an MCL-1 inhibitor synergistically enhanced the anti-proliferative effect in multiple human cancer cell lines. Our study unveiled a rational combination of two previously known inhibitors of the Bcl-2 family for enhanced anti-cancer efficacy and identified a novel activity of gossypol as an inhibitor of CRL1 and CRL5 E3s, thus providing a new possibility in the development of novel CRL inhibitors for anti-cancer therapy.
资助项目	National Key R&D Program of China[2016YFA0501800] ; National Natural Science Foundation of China[81572718] ; National Natural Science Foundation of China[81630076]
WOS关键词	PHASE-II ; PROTEASOME INHIBITORS ; CANCER ; AT-101 ; RESISTANCE ; INCREASES ; CELLS ; MCL-1 ; NOXA ; SENSITIVITY
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	DOVE MEDICAL PRESS LTD
WOS记录号	WOS:000605659500001
资助机构	National Key R&D Program of China ; National Natural Science Foundation of China
内容类型	期刊论文
源URL	[http://ir.hfcas.ac.cn:8080/handle/334002/120071]
专题	中国科学院合肥物质科学研究院
通讯作者	Sun, Yi
作者单位	1.Zhejiang Univ, Sch Med, Affiliated Hosp 2, Canc Inst, 268 Kaixuan Rd, Hangzhou, Zhejiang, Peoples R China 2.Chinese Acad Sci, Inst Basic Med & Canc IBMC, Zhejiang Canc Hosp, Canc Hosp,Univ Chinese Acad Sci,Dept Head & Neck, Hangzhou, Zhejiang, Peoples R China 3.Key Lab Head & Neck Canc Translat Res Zhejiang Pr, Hangzhou, Zhejiang, Peoples R China 4.Zhejiang Univ, Sch Med, Inst Translat Med, 268 Kaixuan Rd, Hangzhou, Zhejiang, Peoples R China
推荐引用方式 GB/T 7714	Yu, Qing,Sun, Yi. Targeting Protein Neddylation to Inactivate Cullin-RING Ligases by Gossypol: A Lucky Hit or a New Start?[J]. DRUG DESIGN DEVELOPMENT AND THERAPY,2021,15.
APA	Yu, Qing,&Sun, Yi.(2021).Targeting Protein Neddylation to Inactivate Cullin-RING Ligases by Gossypol: A Lucky Hit or a New Start?.DRUG DESIGN DEVELOPMENT AND THERAPY,15.
MLA	Yu, Qing,et al."Targeting Protein Neddylation to Inactivate Cullin-RING Ligases by Gossypol: A Lucky Hit or a New Start?".DRUG DESIGN DEVELOPMENT AND THERAPY 15(2021).