title: Redefining the Phenotype of Heat Shock Protein 90 (Hsp90) Inhibitors.
abstract: The phenotypes produced when cells are treated with the heat shock protein 90 (Hsp90) inhibitors AUY922 or 17-AAG (classical inhibitors) are different to those produced when cells are knocked down with Hsp90α. Pull-down assays using classical inhibitors suggest that these molecules bind to multiple targets other than Hsp90. Classical inhibitors also induce similar protein markers as other anti-cancer therapies cisplatin and bortezomib that do not target Hsp90. Together these data suggest that AUY922 and 17-AAG acts on multiple targets and likely kills cells through multiple mechanisms. Comparing these classical inhibitors to the effects seen when treating cells with C-terminal Hsp90 modulators reveals that C-terminal modulators effectively bind to Hsp90, and induce phenotypic markers consistent with the Hsp90α CRISPR knockdown data. Our findings challenge the current interpretation of Hsp90 inhibitors and suggest that a large body of literature that describes the Hsp90 phenotype and inhibitors is re-examined in this context.
authors.affiliation: Department of Medicine, University of New South Wales, Australia.
authors.forename: Yao
authors.initials: Y
authors.lastname: Wang
authors.affiliation: School of Chemistry, University of New South Wales, Sydney, NSW 2052, Australia.
authors.forename: Yen Chin
authors.initials: YC
authors.lastname: Koay
authors.affiliation: School of Chemistry, University of New South Wales, Sydney, NSW 2052, Australia.
authors.forename: Shelli R
authors.identifier: http://orcid.org/0000-0003-1058-5252
authors.initials: SR
authors.lastname: McAlpine
mesh_terms: D016227:Benzoquinones / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D064113:CRISPR-Cas Systems / Q000235:genetics; D055785:Gene Knockdown Techniques; D045325:HCT116 Cells; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006367:HeLa Cells; D000076249:Heat Shock Transcription Factors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007555:Isoxazoles / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D047029:Lactams, Macrocyclic / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D010641:Phenotype; D011485:Protein Binding; D012118:Resorcinols / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C528044:5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide; D016227:Benzoquinones; C000619706:HSF1 protein, human; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; D007555:Isoxazoles; D047029:Lactams, Macrocyclic; D012118:Resorcinols; C112765:tanespimycin
keywords: CRISPR; biological activity; cancer; heat shock protein 90; phenotype