Gossypol inhibits cullin neddylation by targeting SAG-CUL5 and RBX1-CUL1 complexes.
Calcium-Binding Proteins
/ metabolism
Carrier Proteins
/ metabolism
Cell Line, Tumor
Contraceptive Agents, Male
Cullin Proteins
/ genetics
DNA-Binding Proteins
/ metabolism
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Gossypol
/ chemistry
High-Throughput Screening Assays
Humans
Models, Biological
Models, Molecular
Molecular Structure
Multiprotein Complexes
Protein Binding
Protein Processing, Post-Translational
/ drug effects
Structure-Activity Relationship
Tumor Suppressor Proteins
/ metabolism
Cullin-RING E3 ligase
Gossypol
Neddylation
Small molecule inhibitors
Ubiquitin–proteasome system
Journal
Neoplasia (New York, N.Y.)
ISSN: 1476-5586
Titre abrégé: Neoplasia
Pays: United States
ID NLM: 100886622
Informations de publication
Date de publication:
04 2020
04 2020
Historique:
received:
03
10
2019
revised:
09
02
2020
accepted:
10
02
2020
pubmed:
8
3
2020
medline:
18
11
2020
entrez:
8
3
2020
Statut:
ppublish
Résumé
Cullin-RING E3 ligase (CRL) is the largest family of E3 ubiquitin ligase, responsible for ubiquitylation of ∼20% of cellular proteins. CRL plays an important role in many biological processes, particularly in cancers due to abnormal activation. CRL activation requires neddylation, an enzymatic cascade transferring small ubiquitin-like protein NEDD8 to a conserved lysine residue on cullin proteins. Recent studies have validated that neddylation is an attractive anticancer target. In this study, we report the establishment of an Alpha-Screen-based high throughput screen (HTS) assay for in vitro CUL5 neddylation, and screened a library of 17,000 compounds including FDA approved drugs, natural products and synthetic drug-like small-molecule compounds. Gossypol, a natural compound derived from cotton seed, was identified as an inhibitor of cullin neddylation. Biochemical studies showed that gossypol blocked neddylation of both CUL5 and CUL1 through direct binding to SAG-CUL5 or RBX1-CUL1 complex, and CUL5-H572 plays a key role for gossypol binding. On cellular level, gossypol inhibited cullin neddylation in a variety of cancer cell lines and selectively caused accumulation of NOXA and MCL1, the substrates of CUL5 and CUL1, respectively, in multiple cancer cell lines. Combination of gossypol with specific MCL1 inhibitor synergistically suppress growth of human cancer cells. Our study revealed a previously unknown anti-cancer mechanism of gossypol with potential to develop a new class of neddylation inhibitors.
Identifiants
pubmed: 32145688
pii: S1476-5586(19)30393-8
doi: 10.1016/j.neo.2020.02.003
pmc: PMC7076571
pii:
doi:
Substances chimiques
CUL5 protein, human
0
Calcium-Binding Proteins
0
Carrier Proteins
0
Contraceptive Agents, Male
0
Cullin 1
0
Cullin Proteins
0
DMBT1 protein, human
0
DNA-Binding Proteins
0
Multiprotein Complexes
0
RBX1 protein, human
0
Tumor Suppressor Proteins
0
Gossypol
KAV15B369O
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
179-191Informations de copyright
Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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