ReferenceID 5383
Gossypol inhibits cullin neddylation by targeting SAG-CUL5 and RBX1-CUL1 complexes
Neoplasia
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
Relationship Network
Interactive first-hop connections across herbs, ingredients, formulas, targets, diseases, symptoms, syndromes, evidence, and monographs.
Click a node to open it in a new tab
Ingredient: 1Reference: 1Links: 1
Arranging relationship network...
Record Fields
Scalar fields from the final reference record.
- Reference Id
- 5383
- Evidence Id
- 21973
- Core Evidence Id
- 21973
- Source Reference Id
- 4017
- Herb2 Reference Id
- HBREF004814
- Subject Paper Key
- HBIN028351_32145688
- Pubmed Id
- 32145688
- Doi
- 10.1016/j.neo.2020.02.003
- Paper Title
- Gossypol inhibits cullin neddylation by targeting SAG-CUL5 and RBX1-CUL1 complexes
- Paper Abstract
- 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.
- Journal
- Neoplasia
- Publish Year
- 2020
- Experiment Subject
- human; cancer cell lines; multiple cancer cell lines
- Experiment Type
- Cell Experiment
- Phenotype Related
- Cancers; Cancer
- Paper Title Cn
- Paper Title En
- Gossypol inhibits cullin neddylation by targeting SAG-CUL5 and RBX1-CUL1 complexes
- Bilingual Status
- semi_complete