UVR exposure sensitizes keratinocytes to DNA adduct formation

Sudhir Nair, Vikram D. Kekatpure, Benjamin L. Judson, Arleen B. Rifkind, Richard D. Granstein, Jay O. Boyle, Kotha Subbaramaiah, Joseph Guttenplan, Andrew J. Dannenberg

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)895-902
Number of pages8
JournalCancer Prevention Research
Volume2
Issue number10
DOIs
StatePublished - Oct 2009

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Aryl Hydrocarbon Receptors
DNA Adducts
Cytochrome P-450 CYP1A1
Keratinocytes
tanespimycin
Polycyclic Aromatic Hydrocarbons
Radiation
Oral Leukoplakia
Sunlight
Benzo(a)pyrene
Chemoprevention
Smoke
Tryptophan
Tobacco
Radiation Exposure
Carcinogenesis
Ligands
Skin
Proteins

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Nair, S., Kekatpure, V. D., Judson, B. L., Rifkind, A. B., Granstein, R. D., Boyle, J. O., ... Dannenberg, A. J. (2009). UVR exposure sensitizes keratinocytes to DNA adduct formation. Cancer Prevention Research, 2(10), 895-902. https://doi.org/10.1158/1940-6207.CAPR-09-0125

UVR exposure sensitizes keratinocytes to DNA adduct formation. / Nair, Sudhir; Kekatpure, Vikram D.; Judson, Benjamin L.; Rifkind, Arleen B.; Granstein, Richard D.; Boyle, Jay O.; Subbaramaiah, Kotha; Guttenplan, Joseph; Dannenberg, Andrew J.

In: Cancer Prevention Research, Vol. 2, No. 10, 10.2009, p. 895-902.

Research output: Contribution to journalArticle

Nair, S, Kekatpure, VD, Judson, BL, Rifkind, AB, Granstein, RD, Boyle, JO, Subbaramaiah, K, Guttenplan, J & Dannenberg, AJ 2009, 'UVR exposure sensitizes keratinocytes to DNA adduct formation', Cancer Prevention Research, vol. 2, no. 10, pp. 895-902. https://doi.org/10.1158/1940-6207.CAPR-09-0125
Nair S, Kekatpure VD, Judson BL, Rifkind AB, Granstein RD, Boyle JO et al. UVR exposure sensitizes keratinocytes to DNA adduct formation. Cancer Prevention Research. 2009 Oct;2(10):895-902. https://doi.org/10.1158/1940-6207.CAPR-09-0125
Nair, Sudhir ; Kekatpure, Vikram D. ; Judson, Benjamin L. ; Rifkind, Arleen B. ; Granstein, Richard D. ; Boyle, Jay O. ; Subbaramaiah, Kotha ; Guttenplan, Joseph ; Dannenberg, Andrew J. / UVR exposure sensitizes keratinocytes to DNA adduct formation. In: Cancer Prevention Research. 2009 ; Vol. 2, No. 10. pp. 895-902.
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AU - Granstein, Richard D.

AU - Boyle, Jay O.

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