HSP90 Inhibitors Suppress Aryl Hydrocarbon Receptor-Mediated Activation of CYP1A1 and CYP1B1 Transcription and DNA Adduct Formation

• Published in: Cancer prevention research (Philadelphia, Pa.) Pa.), 2008-11, Vol.1 (6), p.485-493
• Main Authors: Hughes, Duncan, Guttenplan, Joseph B., Marcus, Craig B., Subbaramaiah, Kotha, Dannenberg, Andrew J.
• Format: Article
• Language: English
• ISSN: 1940-6207; 1940-6215
• DOI: 10.1158/1940-6207.CAPR-08-0149

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-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 α-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.