Differential regulation of estrogen receptors alpha and beta by 4-(E)-{(4-hydroxyphenylimino)-methylbenzene,1,2-diol}, a novel resveratrol analog.
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Ronghe A, Chatterjee A, Singh B, Dandawate P, Murphy L, Bhat NK, Padhye S, Bhat HK
Differential regulation of estrogen receptors alpha and beta by 4-(E)-{(4-hydroxyphenylimino)-methylbenzene,1,2-diol}, a novel resveratrol analog.
J Steroid Biochem Mol Biol. 2014 Oct;144 Pt B:500-12. doi: 10.1016/j.jsbmb.2014.09.015. Epub 2014 Sep 19.
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- 25242450 [ View in PubMed]
- Abstract
Breast cancer is the second leading cause of death among women in the United States. Estrogens have been implicated as major risk factors in the development of breast neoplasms. Recent epidemiologic studies have suggested a protective role of phytoestrogens in prevention of breast and other cancers. Resveratrol, a naturally occurring phytoestrogen found notably in red grapes, berries and peanuts, has been shown to possess potent anti-cancer properties. However, the poor efficacy of resveratrol has prevented its use in a clinical setting. In order to improve the efficacy of resveratrol, we have synthesized a small combinatorial library of azaresveratrol analogs and tested them for their ability to inhibit the growth of breast cancer cell lines. We have recently shown that one of the synthesized analogs, 4-(E)-{(4-hydroxyphenylimino)-methylbenzene,1,2-diol} (HPIMBD), has better anti-cancer properties than resveratrol. The objective of this study was to investigate the differential regulation of estrogen receptors (ERs) alpha and beta as a potential mechanism of inhibition of breast cancer by HPIMBD. Estrogen receptors alpha and beta have been shown to have opposing roles in cellular proliferation. Estrogen receptor alpha mediates the proliferative responses of estrogens while ERbeta plays an anti-proliferative and pro-apoptotic role. We demonstrate that HPIMBD significantly induces the expression of ERbeta and inhibits the expression of ERalpha. HPIMBD also inhibits the protein expression levels of oncogene c-Myc and cell cycle protein cyclin D1, genes downstream to ERalpha and important regulators of cell cycle, and cellular proliferation. HPIMBD significantly induces protein expression levels of tumor suppressors p53 and p21 in MCF-7 cells. Additionally, HPIMBD inhibits c-Myc in an ERbeta-dependent fashion in MCF-10A and ERbeta1-transfected MDA-MB-231 cells, suggesting regulation of ERs as an important upstream mechanism of this novel compound. Molecular docking studies confirm higher affinity for binding of HPIMBD in the ERbeta cavity. Thus, HPIMBD, a novel azaresveratrol analog may inhibit the proliferation of breast cancer cells by differentially modulating the expressions of ERs alpha and beta.