title: Skp1 in lung cancer: clinical significance and therapeutic efficacy of its small molecule inhibitors.
abstract: 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.
authors.affiliation: State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences & University of Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Yong-Qiang
authors.initials: YQ
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences & University of Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Xiao-Lu
authors.initials: XL
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences & University of Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Cheng
authors.affiliation: State Key Laboratory of Respiratory Disease, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
authors.forename: Yong-Zhi
authors.initials: YZ
authors.lastname: Lu
authors.affiliation: State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences & University of Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Gui-Zhen
authors.initials: GZ
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences & University of Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Xin-Chun
authors.initials: XC
authors.lastname: Li
authors.affiliation: School of Life Sciences, Anhui University, Hefei 230039, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Thoracic Surgery, The Cancer Hospital, Sun Yat-Sen University, Guangzhou 510080, China.
authors.forename: Zhe-Sheng
authors.initials: ZS
authors.lastname: Wen
authors.affiliation: Department of Thoracic Surgery, The Cancer Hospital, Sun Yat-Sen University, Guangzhou 510080, China.
authors.forename: Zhi-Liang
authors.initials: ZL
authors.lastname: Huang
authors.affiliation: State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China.
authors.forename: Qin-Lei
authors.initials: QL
authors.lastname: Gao
authors.affiliation: Shanghai Center for Systems Biomedicine, Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Li-Na
authors.initials: LN
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China.
authors.forename: Yong-Xian
authors.initials: YX
authors.lastname: Cheng
authors.affiliation: Shanghai Center for Systems Biomedicine, Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Sheng-Ce
authors.initials: SC
authors.lastname: Tao
authors.affiliation: State Key Laboratory of Respiratory Disease, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
authors.forename: Jinsong
authors.initials: J
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences & University of Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Guang-Biao
authors.initials: GB
authors.lastname: Zhou
mesh_terms: D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D057166:High-Throughput Screening Assays; D006801:Humans; D047468:Immunoprecipitation; D007783:Lactones / Q000737:chemistry / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000378:metabolism*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D034741:RNA, Small Interfering; D044786:S-Phase Kinase-Associated Proteins / Q000032:analysis / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D012717:Sesquiterpenes / Q000737:chemistry / Q000494:pharmacology*; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: C509025:6-O-angeloylprenolin; D000970:Antineoplastic Agents; D007783:Lactones; D034741:RNA, Small Interfering; D044786:S-Phase Kinase-Associated Proteins; D012717:Sesquiterpenes
keywords: 6-O-angeloylplenolin; Skp1; inhibitors; lung cancer; structure-based high-throughput virtual screening