title: Gambogic acid inhibits Hsp90 and deregulates TNF-α/NF-κB in HeLa cells.
abstract: Gambogic acid (GB) is an important anti-cancer drug candidate, but the target protein by which it exerts its anti-cancer effects has not been identified. This study is the first to show that GB inhibits heat shock protein 90 (Hsp90) and down-regulates TNF-α/NF-κB in HeLa cells. The effects of GB on Hsp90 were studied by characterizing its physical interactions with Hsp90 upon binding, the noncompetitive inhibition of Hsp90 ATPase activity, and the degradation of Hsp90 client proteins (i.e., Akt, IKK) in HeLa cells. GB seems to bind to the N-terminal ATP-binding domain of Hsp90. Additionally, GB suppresses the activation of TNF-α/NF-κB and decreases XIAP expression levels and the ratio of Bcl-2/Bax, which in turn induces HeLa cell apoptosis. Thus, GB represents a promising therapeutic agent for cancer; it may also be useful as a probe to increase understanding of the biological functions of Hsp90.
authors.affiliation: School of Life Sciences, Xiamen University, Xiamen 361005, China. ru898@xmu.edu.cn
authors.forename: Lianru
authors.initials: L
authors.lastname: Zhang
authors.forename: Yuting
authors.initials: Y
authors.lastname: Yi
authors.forename: Junjie
authors.initials: J
authors.lastname: Chen
authors.forename: Yifei
authors.initials: Y
authors.lastname: Sun
authors.forename: Qiuju
authors.initials: Q
authors.lastname: Guo
authors.forename: Zhonghui
authors.initials: Z
authors.lastname: Zheng
authors.forename: Siyang
authors.initials: S
authors.lastname: Song
mesh_terms: D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism*; D011487:Protein Conformation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism; D044004:Xanthones / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D044004:Xanthones; C052659:gambogic acid; D051057:Proto-Oncogene Proteins c-akt; D000251:Adenosine Triphosphatases