Abstract
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.
Highlights
The molecular mechanisms of soy isoflavones in metastatic cancer remain to be elucidated
We show that increased eukaryotic protein synthesis initiation factors (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
Dietary Daidzein Up-regulates Expression of eIF4G and eIF4E and Increased Protein Levels of mRNAs with IRES Sites in Vivo but Not in Vitro—We recently reported that daidzein increased mammary tumor growth and metastasis in nude mice with mammary tumors established from the ER (Ϫ) highly metastatic human cancer cell line MDA-MB-435
Summary
The molecular mechanisms of soy isoflavones in metastatic cancer remain to be elucidated. 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. In ER (ϩ) T47D and MCF-7 human breast cancer cells, equol increased estrogenic activity and cell proliferation, but dietary equol did not affect tumor growth in nude mice (16 –19). Our recent data using ER (Ϫ) highly metastatic MDA-MB435 human cancer cells reported that dietary daidzein and soy isoflavones (daidzein:genistein:glycitein, 5:4:1) increased mammary tumor growth and metastasis in nude mice [30]. PCR analysis of mammary tumors demonstrated that dietary daidzein up-regulated the expression of a number of genes that regulate cell proliferation and survival including CCND1, CTNNB1 (catenin (cadherin-associated protein) 1), GRB2 (growth factor receptor-bound protein 2), JUN (Jun oncogene), MAPK1 (mitogen-activated protein kinase 1), and IRS1 (insulin receptor substrate 1). Equol may direct the synthesis of IRES-containing mRNAs that induce cell survival and cell proliferation and promote cancer malignancy
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