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Heat Shock Protein 90 Inhibitors Suppress Aryl Hydrocarbon Receptor–Mediated Activation of CYP1A1 and CYP1B1 Transcription and DNA Adduct Formation

Authors' Affiliations: Departments of ¹ General Surgery and ² Medicine, Weill Cornell Medical College; ³ Department of Basic Sciences, College of Dentistry; ⁴ Department of Environmental Medicine, School of Medicine, New York University, New York, New York; and ⁵ College of Pharmacy, University of New Mexico, Albuquerque, New Mexico

Requests for reprints: Andrew J. Dannenberg, Department of Medicine and Weill Cornell Cancer Center, 525 East 68th Street, Room F-206, New York, NY 10065. Phone: 212-746-4403; Fax: 212-746-4885; E-mail: ajdannen{at}med.cornell.edu.

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 -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.

Key Words: Heat Shock Protein 90 Inhibitors • Aryl Hydrocarbon Receptor • Tobacco Smoke • Cytochrome P450 • DNA adduct

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