Estrogen Receptor Expression Is Required for Low-Dose Resveratrol-Mediated Repression of Aryl Hydrocarbon Receptor Activity

Abstract

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 (E 2 ) in human MCF-7 breast cancer cells. Unlike E 2 , 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 5Ј-regulatory region of the CYP1A1 gene. Small inhibitory RNAs directed to ER␣ have demonstrated that RES-mediated repression of CYP1A1 depends on ER␣. 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.

Resveratrol improves insulin sensitivity, reduces oxidative stress and activates the Akt pathway in type 2 diabetic patients

“…Whether resveratrol (or some of its future derivatives) becomes a useful tool in combating type 2 diabetes is difficult to tell, although the fact that recent studies (31,32) (including the present study) have demonstrated that the efficacy of resveratrol at low doses might increase the possibility for its medicinal application. On the other hand, the present study definitely suggests that resveratrol could become a useful tool in gaining a deeper understanding of the mechanisms underlying the development of insulin resistance and oxidative stress.…”

Edible flowers — antioxidant activity and impact on cell viability

“…For example, resveratrol [43], detected in a huge amount in V. arvensis flowers and in smaller amounts in R. acetosa, C. intybus, B. perennis, T. officinale and T. pratensis flowers has the ability to bind to both estrogen receptors and act as a mixed agonist/ antagonist. Consequently, resveratrol can have a potent effect, even in low-doses, through the aryl hydrocarbon receptor [44] that plays an important role in cancer cells [45]. Resveratrol not only influences estrogen receptors, but down-regulates the nuclear factor-KB [46], another important therapeutic target.…”

Modulating Potential of L‐Sulforaphane in the Expression of Cytochrome P450 to Identify Potential Targets for Breast Cancer Chemoprevention and Therapy Using Breast Cell Lines

“…In this regard, it was shown that resveratrol in nanomolar concentrations was able to repress AhR‐mediated induction of CYP1A1 in an ERα‐dependent manner without reducing the level of AhR complex at the CYP1A1 promoter. In contrast, 10 μM of resveratrol markedly reduced AhR complex on the CYP1A1 promoter and resulted in near‐complete inhibition of CYP1A1 expression and metabolic activity [Perdew et al , ]. Thus, further studies including cross talk between ERα and AhR also using nanomolar SFN concentrations are necessary to explain the mechanism of the inhibition or induction of CYPs involved in estrogen catabolism.…”