UVR exposure sensitizes keratinocytes to DNA adduct formation.
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. alphaNF, 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 alpha-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.
Department of Medicine and Weill Cornell Cancer Center, 525 East 68th Street, Room F-206, New York, NY 10065, USA.
Sudhir
S
Nair
Vikram D
VD
Kekatpure
Benjamin L
BL
Judson
Arleen B
AB
Rifkind
Richard D
RD
Granstein
Jay O
JO
Boyle
Kotha
K
Subbaramaiah
Joseph B
JB
Guttenplan
Andrew J
AJ
Dannenberg
D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis / Q000528:radiation effects; D002460:Cell Line; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis / Q000528:radiation effects; D065633:Cytochrome P-450 CYP1B1; D018736:DNA Adducts / Q000528:radiation effects*; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects* / Q000528:radiation effects*; D011084:Polycyclic Aromatic Hydrocarbons / Q000009:adverse effects / Q000528:radiation effects*; D018336:Receptors, Aryl Hydrocarbon / Q000528:radiation effects*; D015398:Signal Transduction / Q000528:radiation effects; D014158:Transcription, Genetic / Q000528:radiation effects; D014466:Ultraviolet Rays / Q000009:adverse effects*
D018736:DNA Adducts; D011084:Polycyclic Aromatic Hydrocarbons; D018336:Receptors, Aryl Hydrocarbon; C095911:polycyclic aromatic hydrocarbons-DNA adduct; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; D019363:Cytochrome P-450 CYP1A1; D065633:Cytochrome P-450 CYP1B1