Journal
ONCOTARGET
Volume 6, Issue 33, Pages 34953-34967Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.5547
Keywords
Skp1; lung cancer; structure-based high-throughput virtual screening; inhibitors; 6-O-angeloylplenolin
Categories
Funding
- National Natural Science Funds for Distinguished Young Scholar [81425025]
- National Key Program for Basic Research [2012CB910800]
- National Natural Science Foundation [81071930, 81171925, 81201537, 31000388]
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Skp1 is an essential adaptor protein of the Skp1-Cul1-F-box protein complex and is able to stabilize the conformation of some ubiquitin E3 ligases. However, the role Skp1 plays during tumorigenesis remains unclear and Skp1-targeting agent is lacking. Here we showed that Skp1 was overexpressed in 36/64 (56.3%) of non-small cell lung cancers, and elevated Skp1 was associated with poor prognosis. By structure-based high-throughput virtual screening, we found some Skp1-targeting molecules including a natural compound 6-O-angeloylplenolin (6-OAP). 6-OAP bound Skp1 at sites critical to Skp1-Skp2 interaction, leading to dissociation and proteolysis of oncogenic E3 ligases NIPA, Skp2, and beta-TRCP, and accumulation of their substrates Cyclin B1, P27 and E-Cadherin. 6-OAP induced prometaphase arrest and exerted potent anti-lung cancer activity in two murine models and showed low adverse effect. These results indicate that Skp1 is critical to lung cancer pathogenesis, and Skp1 inhibitor inactivates crucial oncogenic E3 ligases and exhibits significant therapeutic potentials.
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