RT Journal Article
SR Electronic
T1 Estrogen Receptor Expression Is Required for Low-Dose Resveratrol-Mediated Repression of Aryl Hydrocarbon Receptor Activity
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 273
OP 283
DO 10.1124/jpet.110.170654
VO 335
IS 2
A1 Gary H. Perdew
A1 Brett D. Hollingshead
A1 Brett C. DiNatale
A1 J. Luis Morales
A1 Mark P. Labrecque
A1 Mandeep K. Takhar
A1 Kevin J. Tam
A1 Timothy V. Beischlag
YR 2010
UL http://jpet.aspetjournals.org/content/335/2/273.abstract
AB The putative cardioprotective and chemopreventive properties of the red wine phenolic resveratrol (RES) have made it the subject of a growing body of clinical and basic research. We have begun investigations focusing on the effects of RES on the activity of the aryl hydrocarbon receptor (AHR) complex. Our evidence suggests that RES is a potent repressor of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-inducible gene transcription in estrogen receptor (ER)-positive human breast, lung, and colon cancer cell lines. RES activates the transcription of the ER target genes to the same degree as estradiol (E2) in human MCF-7 breast cancer cells. Unlike E2, which can only diminish TCDD-inducible CYP1A1 gene transcription by approximately 50%, RES can completely abrogate this response. Furthermore, 50% repression of TCDD-inducible transcription can be achieved with 100 nM RES, approximately 2.5 orders of magnitude lower than concentrations required for maximal inhibition, suggesting that multiple mechanisms are responsible for this effect. RES (100 nM) does not prevent ligand binding of a TCDD analog, nor does it prevent AHR from binding to its response element in the 5′-regulatory region of the CYP1A1 gene. Small inhibitory RNAs directed to ERα have demonstrated that RES-mediated repression of CYP1A1 depends on ERα. Whereas CYP1A1 protein levels in MCF-7 cells are refractory to the low-dose transcriptional effects of RES, a concomitant decrease in CYP1A1 protein levels is observed in Caco-2 cells. These results highlight a low-dose RES effect that could occur at nutritionally relevant exposures and are distinct from the high-dose effects often characterized.