title: Quantitative proteomics reveals molecular mechanism of gamabufotalin and its potential inhibition on Hsp90 in lung cancer.
abstract: Gamabufotalin (CS-6) is a major bufadienolide of Chansu, which shows desirable metabolic stability and less adverse effect in cancer therapy. CS-6 treatment inhibited the proliferation of NSCLC in a nanomolar range. And CS-6 could induce G2/M cell cycle arrest and apoptosis in A549 cells. However, its molecular mechanism in antitumor activity remains poorly understood. We employed a quantitative proteomics approach to identify the potential cellular targets of CS-6, and found 38 possible target-related proteins. Among them, 31 proteins were closely related in the protein-protein interaction network. One of the regulatory nodes in key pathways was occupied by Hsp90. Molecular docking revealed that CS-6 interacted with the ATP-binding sites of Hsp90. In addition, CS-6 inhibited the chaperone function of Hsp90 and reduced expression of Hsp90-dependent client proteins. Moreover, CS-6 markedly down-regulated the protein level of Hsp90 in tumor tissues of the xenograft mice. Taken together, our results suggest that CS-6 might be a novel inhibitor of Hsp90, and the possible network associated with CS-6 target-related proteins was constructed, which provided experimental evidence for the preclinical value of using CS-6 as an effective antitumor agent in treatment of NSCLC.
authors.affiliation: Dalian Medical University, Dalian, China.
authors.forename: Liyuan
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Dalian Medical University, Dalian, China.|Department of Pharmacy and Traditional Chinese Medicine, Chinese People's Liberation Army 210 Hospital, Dalian, China.
authors.forename: Zhenlong
authors.initials: Z
authors.lastname: Yu
authors.affiliation: Dalian Medical University, Dalian, China.|Department of Pharmacy and Traditional Chinese Medicine, Chinese People's Liberation Army 210 Hospital, Dalian, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pharmacy and Traditional Chinese Medicine, Chinese People's Liberation Army 210 Hospital, Dalian, China.
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Wang
authors.affiliation: State Key Lab of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, China.
authors.forename: Lianru
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Dalian Medical University, Dalian, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Wang
authors.affiliation: Dalian Medical University, Dalian, China.|Institute of Oncology, Shanghai 9th People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China.
authors.forename: Qingxi
authors.initials: Q
authors.lastname: Yue
authors.affiliation: Department of Nuerosurgery, The Third People's Hospital of Dalian, Non-Directly Affiliated Hospital of Dalian Medical University, Dalian, China.
authors.forename: Xun
authors.initials: X
authors.lastname: Wang
authors.affiliation: Dalian Medical University, Dalian, China.
authors.forename: Sa
authors.initials: S
authors.lastname: Deng
authors.affiliation: Dalian Medical University, Dalian, China.
authors.forename: Xiaokui
authors.initials: X
authors.lastname: Huo
authors.affiliation: Dalian Medical University, Dalian, China.
authors.forename: Xiangge
authors.initials: X
authors.lastname: Tian
authors.affiliation: Dalian Medical University, Dalian, China.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Huang
authors.affiliation: Dalian Medical University, Dalian, China.
authors.forename: Baojing
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Dalian Medical University, Dalian, China.
authors.forename: Xiaochi
authors.initials: X
authors.lastname: Ma
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D002018:Bufanolides / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002853:Chromatography, Liquid; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism*; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D040901:Proteomics / Q000379:methods; D021281:Quantitative Structure-Activity Relationship; D053719:Tandem Mass Spectrometry
chemical_list: D000970:Antineoplastic Agents; D002018:Bufanolides; D018841:HSP90 Heat-Shock Proteins; C000612263:gamabufotalin
keywords: NSCLC; gamabufotalin; gene ontology (GO); heat shock protein 90 (Hsp90); quantitative proteomics