The Major Cyclic Trimeric Product of Indole-3-carbinol Is a Strong Agonist of the Estrogen Receptor Signaling Pathway

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• 作者：Jacques E. Riby ; Chunling Feng ; Yu-Chen Chang ; Charlene M. Schaldach ; Gary L. Firestone ; and Leonard F. Bjeldanes
• 刊名：Biochemistry
• 出版年：2000
• 出版时间：February 8, 2000
• 年：2000
• 卷：39
• 期：5
• 页码：910 - 918
• 全文大小：323K
• 年卷期：v.39,no.5(February 8, 2000)
• ISSN：1520-4995

文摘

Indole-3-carbinol (I3C), a component of Brassica vegetables, is under study as a preventiveagent of cancers of the breast and other organs. Following ingestion, I3C is converted to a series ofoligomeric products that presumably are responsible for the in vivo effects of I3C. We report the effectsof the major trimeric product, 5,6,11,12,17,18-hexahydrocyclonona[1,2-b:4,5-b':7,8-b' ']triindole (CTr),on the estrogen receptor (ER) signaling pathways. Tumor-promoting effects of high doses of I3C may bedue to activation of aryl hydrocarbon receptor (AhR)-mediated pathways; therefore, we also examinedthe effects of CTr on AhR activated processes. We observed that CTr is a strong agonist of ER function.CTr stimulated the proliferation of estrogen-responsive MCF-7 cells to a level similar to that produced byestradiol (E₂) but did not affect the growth of the estrogen-independent cell line, MDA-MD-231. CTrdisplaced E₂ in competitive-binding studies and activated ER-binding to an estrogen responsive DNAelement in gel mobility shift assays with EC₅₀s of about 0.1 M. CTr activated transcription of an E₂-responsive endogenous gene and exogenous reporter genes in transfected MCF-7 cells, also with highpotency. CTr failed to activate AhR-mediated pathways, consistent with the low-binding affinity of CTrfor the AhR reported previously. Comparisons of the conformational characteristics of CTr with other ERligands indicated a remarkable similarity with tamoxifen, a selective ER antagonist used as a breast cancertherapeutic agent and suggest an excellent fit of CTr into the ligand-binding site of the ER.