title: Heat shock protein 90 (HSP90) inhibitors activate the heat shock factor 1 (HSF1) stress response pathway and improve glucose regulation in diabetic mice.
abstract: The cytoprotective stress response factor HSF1 regulates the transcription of the chaperone HSP70, which exhibits anti-inflammatory effects and improves insulin sensitivity. We tested the therapeutic potential of this pathway in rodent models of diabetes using pharmacological tools. Activation of the HSF1 pathway was achieved using potent inhibitors of the upstream regulatory protein, HSP90. Treatment with AUY922, a selective HSP90 inhibitor led to robust inhibition of JNK1 phosphorylation, cytoprotection and improved insulin signaling in cells, consistent with effects observed with HSP70 treatment. Chronic dosing with HSP90 inhibitors reversed hyperglycemia in the diabetic db/db mouse model, and improved insulin sensitivity in the diet-induced obese mouse model of insulin resistance, further supporting the concept that the HSF1 pathway is a potentially viable anti-diabetes target.
authors.affiliation: Cardiovascular and Metabolism Disease Area, Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
authors.forename: Jee-Hyung
authors.initials: JH
authors.lastname: Lee
authors.forename: Jiaping
authors.initials: J
authors.lastname: Gao
authors.forename: Penelope A
authors.initials: PA
authors.lastname: Kosinski
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Elliman
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Hughes
authors.forename: Jesper
authors.initials: J
authors.lastname: Gromada
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Kemp
mesh_terms: D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology; D001786:Blood Glucose / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D019610:Cytoprotection; D004268:DNA-Binding Proteins / Q000819:agonists*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D000076249:Heat Shock Transcription Factors; D018869:Heat-Shock Response; D007004:Hypoglycemic Agents / Q000008:administration & dosage*; D007555:Isoxazoles / Q000008:administration & dosage* / Q000737:chemistry; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D032446:Myoblasts / Q000187:drug effects / Q000378:metabolism; D012118:Resorcinols / Q000008:administration & dosage* / Q000737:chemistry; D014157:Transcription Factors / Q000819:agonists*
chemical_list: C528044:5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide; D016227:Benzoquinones; D001786:Blood Glucose; D004268:DNA-Binding Proteins; D018841:HSP90 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; C490017:Hsf1 protein, mouse; D007004:Hypoglycemic Agents; D007555:Isoxazoles; D047029:Lactams, Macrocyclic; D012118:Resorcinols; D014157:Transcription Factors; C001277:geldanamycin