Involvement of a post-transcriptional mechanism in the inhibition of CYP1A1 expression by resveratrol in breast cancer cells.
Resveratrol decreases basal and induced CYP1A1 mRNA/protein levels in both in vitro and in vivo models, and some studies suggest that resveratrol acts as an aryl hydrocarbon receptor (AhR) antagonist. Treatment of T47D or MCF-7 cells with 10 microM resveratrol inhibited induction of CYP1A1 mRNA and CYP1A1-dependent activity after treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), as previously reported. In contrast, resveratrol did not inhibit TCDD-induced reporter gene activity in cells transfected with an Ah-responsive construct containing a human CYP1A1 gene promoter insert, whereas 3'-methoxy-4'-nitroflavone, a "pure" AhR antagonist, inhibited this response. Resveratrol induced transformation of the rat cytosolic AhR and, after treatment of T47D and MCF-7 cells with resveratrol, a transformed nuclear AhR complex was observed. In contrast to 3'-methoxy-4'-nitroflavone, resveratrol did not block TCDD-induced AhR transformation in vitro or nuclear uptake of the AhR complex in breast cancer cells. Thus, the action of resveratrol on the AhR was consistent with that of an AhR agonist; however, resveratrol did not exhibit functional AhR agonist or antagonist activities in breast cancer cells. Actinomycin D chase experiments in T47D cells showed that resveratrol and dehydroepiandrosterone both increased the rate of CYP1A1 mRNA degradation, whereas resveratrol did not affect CYP1A1-dependent activity in cells pretreated with TCDD for 18 hr. These data suggest that resveratrol inhibits CYP1A1 via an AhR-independent post-transcriptional pathway.
Lee
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JE
Department of Veterinary Physiology & Pharmacology, Texas A&M University, 4466 TAMU, College Station, TX 77843-4466, USA.
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D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000473:pathology; D019363:Cytochrome P-450 CYP1A1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D004795:Enzyme Stability / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects*; D006801:Humans; D012323:RNA Processing, Post-Transcriptional; D020871:RNA Stability / Q000187:drug effects*; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000972:Antineoplastic Agents, Phytogenic; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D013267:Stilbenes; D019363:Cytochrome P-450 CYP1A1; D000077185:Resveratrol