Department of Biochemistry, School of Medicine, University of Puerto Rico, Medical Sciences Campus, San Juan, Puerto Rico.
J Biol Chem. 2012 Dec 7;287(50):41640-50. doi: 10.1074/jbc.M112.393470. Epub 2012 Oct 24.
Dietary soy is thought to be cancer-preventive; however, the beneficial effects of soy on established breast cancer is controversial. We recently demonstrated that dietary daidzein or combined soy isoflavones (genistein, daidzein, and glycitein) increased primary mammary tumor growth and metastasis. Cancer-promoting molecules, including eukaryotic protein synthesis initiation factors (eIF) eIF4G and eIF4E, were up-regulated in mammary tumors from mice that received dietary daidzein. Herein, we show that increased eIF expression in tumor extracts of mice after daidzein diets is associated with protein expression of mRNAs with internal ribosome entry sites (IRES) that are sensitive to eIF4E and eIF4G levels. Results with metastatic cancer cell lines show that some of the effects of daidzein in vivo can be recapitulated by the daidzein metabolite equol. In vitro, equol, but not daidzein, up-regulated eIF4G without affecting eIF4E or its regulator, 4E-binding protein (4E-BP), levels. Equol also increased metastatic cancer cell viability. Equol specifically increased the protein expression of IRES containing cell survival and proliferation-promoting molecules and up-regulated gene and protein expression of the transcription factor c-Myc. Moreover, equol increased the polysomal association of mRNAs for p 120 catenin and eIF4G. The elevated eIF4G in response to equol was not associated with eIF4E or 4E-binding protein in 5' cap co-capture assays or co-immunoprecipitations. In dual luciferase assays, IRES-dependent protein synthesis was increased by equol. Therefore, up-regulation of eIF4G by equol may result in increased translation of pro-cancer mRNAs with IRESs and, thus, promote cancer malignancy.
膳食大豆被认为具有防癌作用；然而，大豆对已确诊乳腺癌的有益影响仍存在争议。我们最近的研究表明，膳食大豆异黄酮（染料木黄酮、大豆苷元和黄豆黄素）或其混合物可促进原发性乳腺癌肿瘤的生长和转移。在接受膳食染料木黄酮的小鼠的乳腺肿瘤中，上调了促进癌症的分子，包括真核蛋白合成起始因子（eIF）eIF4G 和 eIF4E。本文中，我们发现，小鼠接受染料木黄酮饮食后，肿瘤提取物中 eIF 的表达增加与具有内部核糖体进入位点（IRES）的 mRNA 的蛋白表达相关，这些 mRNA 对 eIF4E 和 eIF4G 的水平敏感。转移性癌细胞系的研究结果表明，染料木黄酮代谢物黄豆黄素可部分再现体内染料木黄酮的作用。在体外，黄豆黄素可上调 eIF4G，而不影响 eIF4E 或其调节因子 4E 结合蛋白（4E-BP）的水平。黄豆黄素还增加了转移性癌细胞的活力。黄豆黄素特异性地上调了含有 IRES 的细胞生存和增殖促进分子的蛋白表达，并上调了转录因子 c-Myc 的基因和蛋白表达。此外，黄豆黄素还增加了 p120 连环蛋白和 eIF4G 的多核糖体结合。在 5' 帽共捕获测定或共免疫沉淀中，与黄豆黄素反应而升高的 eIF4G 与 eIF4E 或 4E 结合蛋白无关。在双荧光素酶测定中，黄豆黄素增加了 IRES 依赖的蛋白合成。因此，黄豆黄素对 eIF4G 的上调可能导致含有 IRES 的促癌 mRNA 的翻译增加，从而促进癌症恶性程度的提高。
