title: Heat shock protein 90 inhibitors suppress aryl hydrocarbon receptor-mediated activation of CYP1A1 and CYP1B1 transcription and DNA adduct formation.
abstract: The aryl hydrocarbon receptor (AhR), a client protein of heat shock protein 90 (HSP90), plays a significant role in polycyclic aromatic hydrocarbon (PAH)-induced carcinogenesis. Tobacco smoke, a source of PAHs, activates the AhR, leading to enhanced transcription of CYP1A1 and CYP1B1, which encode proteins that convert PAHs to genotoxic metabolites. The main objectives of this study were to determine whether HSP90 inhibitors suppress PAH-mediated induction of CYP1A1 and CYP1B1 or block benzo(a)pyrene [B(a)P]-induced formation of DNA adducts. Treatment of cell lines derived from oral leukoplakia (MSK-Leuk1) or esophageal squamous cell carcinoma (KYSE450) with a saline extract of tobacco smoke, B(a)P, or dioxin induced CYP1A1 and CYP1B1 transcription, resulting in enhanced levels of message and protein. Inhibitors of HSP90 [17-allylamino-17-demethoxygeldanamycin (17-AAG); celastrol] suppressed these inductive effects of PAHs. Treatment with 17-AAG and celastrol also caused a rapid and marked decrease in amounts of AhR protein without modulating levels of HSP90. The formation of B(a)P-induced DNA adducts in MSK-Leuk1 cells was inhibited by 17-AAG, celastrol, and alpha-naphthoflavone, a known AhR antagonist. The reduction in B(a)P-induced DNA adducts was due, at least in part, to reduced metabolic activation of B(a)P. Collectively, these results suggest that 17-AAG and celastrol, inhibitors of HSP90, suppress the activation of AhR-dependent gene expression, leading, in turn, to reduced formation of B(a)P-induced DNA adducts. Inhibitors of HSP90 may have a role in chemoprevention in addition to cancer therapy.
authors.affiliation: Departments of 1General Surgery, Weill Cornell Medical College, New York University, New York, New York 10065, USA.
authors.forename: Duncan
authors.initials: D
authors.lastname: Hughes
authors.forename: Joseph B
authors.initials: JB
authors.lastname: Guttenplan
authors.forename: Craig B
authors.initials: CB
authors.lastname: Marcus
authors.forename: Kotha
authors.initials: K
authors.lastname: Subbaramaiah
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Dannenberg
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D016227:Benzoquinones / Q000494:pharmacology* / Q000627:therapeutic use; D002294:Carcinoma, Squamous Cell / Q000201:enzymology / Q000235:genetics / Q000517:prevention & control; D002478:Cells, Cultured; D018890:Chemoprevention / Q000379:methods; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics / Q000378:metabolism*; D065633:Cytochrome P-450 CYP1B1; D018736:DNA Adducts / Q000187:drug effects / Q000378:metabolism*; D004353:Drug Evaluation, Preclinical; D004789:Enzyme Activation / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006258:Head and Neck Neoplasms / Q000201:enzymology / Q000235:genetics / Q000517:prevention & control; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology* / Q000627:therapeutic use; D008954:Models, Biological; D053978:Pentacyclic Triterpenes; D011230:Precancerous Conditions / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D018336:Receptors, Aryl Hydrocarbon / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D014158:Transcription, Genetic / Q000187:drug effects; D014315:Triterpenes / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D016227:Benzoquinones; D018736:DNA Adducts; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D053978:Pentacyclic Triterpenes; D018336:Receptors, Aryl Hydrocarbon; D014315:Triterpenes; C112765:tanespimycin; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; D019363:Cytochrome P-450 CYP1A1; D065633:Cytochrome P-450 CYP1B1; C050414:celastrol