Skp1 in lung cancer: clinical significance and therapeutic efficacy of its small molecule inhibitors
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Yong-Qiang Liu1,*, Xiao-Lu Wang1,*, Xin Cheng1,*, Yong-Zhi Lu2,*, Gui-Zhen Wang1,*, Xin-Chun Li1, Jian Zhang3, Zhe-Sheng Wen4, Zhi-Liang Huang4, Qin-Lei Gao5, Li-Na Yang6, Yong-Xian Cheng5, Sheng-Ce Tao6, Jinsong Liu2, Guang-Biao Zhou1
1State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences & University of Chinese Academy of Sciences, Beijing 100101, China
2State Key Laboratory of Respiratory Disease, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
3School of Life Sciences, Anhui University, Hefei 230039, China
4Department of Thoracic Surgery, the Cancer Hospital, Sun Yat-Sen University, Guangzhou 510080, China
5State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China
6Shanghai Center for Systems Biomedicine, Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200240, China
*These authors have contributed equally to this work
Guang-Biao Zhou, e-mail: [email protected]
Jinsong Liu, e-mail: [email protected]
Yong-Xian Cheng, e-mail: [email protected]
Keywords: Skp1, lung cancer, structure-based high-throughput virtual screening, inhibitors, 6-O-angeloylplenolin
Received: July 17, 2015 Accepted: September 10, 2015 Published: October 12, 2015
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 β-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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