期刊
DRUG DESIGN DEVELOPMENT AND THERAPY
卷 15, 期 -, 页码 1-8出版社
DOVE MEDICAL PRESS LTD
DOI: 10.2147/DDDT.S286373
关键词
anti-cancer drug; cullin-RING E3 ligases; natural product; high-throughput screen; neddylation; small-molecule inhibitors
资金
- National Key R&D Program of China [2016YFA0501800]
- National Natural Science Foundation of China [81572718, 81630076]
Cullin-RING E3 ligases (CRLs) are the largest family of E3 ubiquitin ligases, responsible for about 20% of protein degradation by the ubiquitin-proteasome system. Gossypol, a natural product extracted from cottonseeds, was identified as a potent inhibitor of cullin-1 and cullin-5 neddylation, leading to the accumulation of MCL-1 and NOXA, substrates of CRL1 and CRL5, respectively. The combination of gossypol and an MCL-1 inhibitor showed synergistic anti-proliferative effects in multiple human cancer cell lines, suggesting a promising strategy for anti-cancer therapy.
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.
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