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United States Department of Agriculture

Agricultural Research Service

Title: Genistein Affects Androgen-Responsive Genes Through Both Androgen Receptor and Estrogen Receptor-Mediated Pathways

Authors
item Takahashi, Yoko
item Hursting, Stephen - NCI/NIH,BETHESDA, MD
item Perkins, Susan - NCI/NIH,BETHESDA, MD
item Wang, Thomas

Submitted to: Molecular Carcinogenesis
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: June 6, 2005
Publication Date: December 13, 2006
Citation: Takahashi, Y., Hursting, S.D., Perkins, S.N., Wang, T.T. 2006. Genistein affects androgen-responsive genes through both androgen receptor- and estrogen receptor-mediated pathways. Molecular Carcinogenesis. 45:18-25.

Interpretive Summary: Many studies have correlated the consumption of soy-rich diets with a decreased risk of developing hormone-dependent cancers, including prostate cancer. Genistein is a candidate prostate cancer preventive phytochemical found at high levels in soybeans and soy foods. To better understand the molecular mechanisms underlying the beneficial effects of genistein on prostate cancer prevention, we utilized cell culture model to examine the mechanism of genistein's actions. Expression of androgen- and estrogen-regulated genes was measured in LNCaP cells cultured in the presence or absence of hormonal stimulation and the presence or absence of genistein. Genistein strongly suppressed basal expression of androgen-responsive gene (ARG) mRNAs, including prostate specific antigen (PSA) and Ste20-related proline-alanine rich kinase (SPAK), in LNCaP cells grown in 10% FBS. However, genistein had little or no effect on basal expression of two other ARGs beta2-microglobulin (B2M) or selenoprotein P (SEPP1) mRNA under similar cell growth conditions. Culturing LNCaP cells in the presence of the synthetic androgen R1881 induced increases in PSA, SPAK, B2M and SEPP1 mRNAs. The R1881-induced expression of these genes was uniformly blocked by genistein. For PSA and SPAK, genistein also blocked or down-regulated 17beta-estradiol-induced increases in mRNA expression. These results indicate that genistein selectively alters expression of ARG mRNAs in LNCaP cells through modulation of both androgen- and estrogen-induced signaling pathway. Based on these results, we proposed that the regulation of androgen receptor- as well as estrogen receptor-mediated events is potentially relevant chemopreventive mechanism for genistein administered at physiologic levels. This work provide novel information for cancer research scientist regarding molecular targets and mechanism(s) of action of soy-derived phytochemical(s) and will serve as important bases for future design of cancer preventive strategy. This work will benefit basic as well as translational research scientist.

Technical Abstract: This study examines the mechanisms by which the prostate cancer chemopreventive agent genistein modulates gene expression in LNCaP human prostate cancer cells. Expression of androgen- and estrogen-regulated genes was measured in LNCaP cells cultured in the presence or absence of hormonal stimulation and the presence or absence of genistein. Genistein strongly suppressed basal expression of androgen-responsive gene (ARG) mRNAs, including prostate specific antigen (PSA) and Ste20-related proline-alanine rich kinase (SPAK), in LNCaP cells grown in 10% FBS. However, genistein had little or no effect on basal expression of two other ARGs '2-microglobulin ('2M) or selenoprotein P (SEPP1) mRNA under similar cell growth conditions. Culturing LNCaP cells in the presence of the synthetic androgen R1881 induced increases in PSA, SPAK, B2M and SEPP1 mRNAs. The R1881-induced expression of these genes was uniformly blocked by genistein. For PSA and SPAK, genistein also blocked or down-regulated 17'-estradiol-induced increases in mRNA expression. These results indicate that genistein selectively alters expression of ARG mRNAs in LNCaP cells through modulation of both androgen- and estrogen-induced signaling pathways.

Last Modified: 11/28/2014
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