UVR exposure sensitizes keratinocytes to DNA adduct formation Journal Article
| Authors: | Nair, S.; Kekatpure, V. D.; Judson, B. L.; Rifkind, A. B.; Granstein, R. D.; Boyle, J. O.; Subbaramaiah, K.; Guttenplan, J. B.; Dannenberg, A. J. |
| Article Title: | UVR exposure sensitizes keratinocytes to DNA adduct formation |
| Abstract: | UV radiation (UVR) and exposure to tobacco smoke, a source of polycyclic aromatic hydrocarbons (PAH), have been linked to skin carcinogenesis. UVR-mediated activation of the aryl hydrocarbon receptor (AhR) stimulates the transcription of CYP1A1 and CYP1B1, which encode proteins that convert PAH to genotoxic metabolites. We determined whether UVR exposure sensitized human keratinocytes to PAH-induced DNA adduct formation. UVR exposure induced CYP1A1 and CYP1B1 in HaCaT cells, an effect that was mimicked by photooxidized tryptophan (aTRP) and FICZ, a component of aTRP. UVR exposure or pretreatment with aTRP or FICZ also sensitized cells to benzo(a)pyrene (B[a]P)-induced DNA adduct formation. αNF, an AhR antagonist, suppressed UVR-, aTRP-, and FICZ-mediated induction of CYP1A1 and CYP1B1 and inhibited B[a]P-induced DNA adduct formation. Treatment with 17-AAG, an Hsp90 inhibitor, caused a marked decrease in levels of AhR; inhibited UVR-, aTRP-, and FICZ-mediated induction of CYP1A1 and CYP1B1; and blocked the sensitization of HaCaT cells to B[a]P-induced DNA adduct formation. FICZ has been suggested to be a physiologic ligand of the AhR that may have systemic effects. Hence, studies of FICZ were also carried out in MSK-Leuk1 cells, a model of oral leukoplakia. Pretreatment with α-naphthoflavone or 17-AAG blocked FICZ-mediated induction of CYP1A1 and CYP1B1, and suppressed the increased B[a]P-induced DNA adduct formation. Collectively, these results suggest that sunlight may activate AhR signaling and thereby sensitize cells to PAH-mediated DNA adduct formation. Antagonists of AhR signaling may have a role in the chemoprevention of photocarcinogenesis. ©2009 American Association for Cancer Research. |
| Keywords: | signal transduction; ultraviolet radiation; chemoprophylaxis; cell line; transcription, genetic; keratinocyte; radiation exposure; heat shock protein 90 inhibitor; tanespimycin; benzo[a]pyrene; dna adduct; dna adducts; aryl hydrocarbon hydroxylases; cytochrome p450 1b1; ultraviolet rays; keratinocytes; alpha naphthoflavone; aromatic hydrocarbon receptor; cytochrome p450 1a1; polycyclic aromatic hydrocarbon derivative; tryptophan; enzyme induction; leukoplakia; radiation carcinogenesis; cytochrome p-450 cyp1a1; polycyclic hydrocarbons, aromatic; receptors, aryl hydrocarbon |
| Journal Title: | Cancer Prevention Research |
| Volume: | 2 |
| Issue: | 10 |
| ISSN: | 1940-6207 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2009-10-01 |
| Start Page: | 895 |
| End Page: | 902 |
| Language: | English |
| DOI: | 10.1158/1940-6207.capr-09-0125 |
| PUBMED: | 19789301 |
| PROVIDER: | scopus |
| PMCID: | PMC2758323 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 1" - "Export Date: 30 November 2010" - "Source: Scopus" |
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