title: Equol, an isoflavone metabolite, regulates cancer cell viability and protein synthesis initiation via c-Myc and eIF4G.
abstract: Epidemiological studies implicate dietary soy isoflavones as breast cancer preventives, especially due to their anti-estrogenic properties. However, soy isoflavones may also have a role in promoting breast cancer, which has yet to be clarified. We previously reported that equol, a metabolite of the soy isoflavone daidzein, may advance breast cancer potential via up-regulation of the eukaryotic initiation factor 4GI (eIF4GI). In estrogen receptor negative (ER-) metastatic breast cancer cells, equol induced elevated levels of eIF4G, which were associated with increased cell viability and the selective translation of mRNAs that use non-canonical means of initiation, including internal ribosome entry site (IRES), ribosome shunting, and eIF4G enhancers. These mRNAs typically code for oncogenic, survival, and cell stress molecules. Among those mRNAs translationally increased by equol was the oncogene and eIF4G enhancer, c-Myc. Here we report that siRNA-mediated knockdown of c-Myc abrogates the increase in cancer cell viability and mammosphere formation by equol, and results in a significant down-regulation of eIF4GI (the major eIF4G isoform), as well as reduces levels of some, but not all, proteins encoded by mRNAs that are translationally stimulated by equol treatment. Knockdown of eIF4GI also markedly reduces an equol-mediated increase in IRES-dependent mRNA translation and the expression of specific oncogenic proteins. However, eIF4GI knockdown did not reciprocally affect c-Myc levels or cell viability. This study therefore implicates c-Myc as a potential regulator of the cancer-promoting effects of equol via up-regulation of eIF4GI and selective initiation of translation on mRNAs that utilize non-canonical initiation, including certain oncogenes.
authors.affiliation: From the Department of Biochemistry, School of Medicine, University of Puerto Rico, Medical Sciences Campus, San Juan, Puerto Rico 00936 and Department of Microbiology and Radiation Oncology, NYU Cancer Institute, New York University School of Medicine, New York, New York 10016.
authors.forename: Columba
authors.initials: C
authors.lastname: de la Parra
authors.affiliation: From the Department of Biochemistry, School of Medicine, University of Puerto Rico, Medical Sciences Campus, San Juan, Puerto Rico 00936 and.
authors.forename: Luis D
authors.initials: LD
authors.lastname: Borrero-Garcia
authors.affiliation: From the Department of Biochemistry, School of Medicine, University of Puerto Rico, Medical Sciences Campus, San Juan, Puerto Rico 00936 and.
authors.forename: Ailed
authors.initials: A
authors.lastname: Cruz-Collazo
authors.affiliation: Department of Microbiology and Radiation Oncology, NYU Cancer Institute, New York University School of Medicine, New York, New York 10016.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Schneider
authors.affiliation: From the Department of Biochemistry, School of Medicine, University of Puerto Rico, Medical Sciences Campus, San Juan, Puerto Rico 00936 and su.d@upr.edu.
authors.forename: Suranganie
authors.initials: S
authors.lastname: Dharmawardhane
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D060754:Equol / Q000008:administration & dosage*; D039603:Eukaryotic Initiation Factor-4G / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D007529:Isoflavones / Q000008:administration & dosage*; D014176:Protein Biosynthesis / Q000187:drug effects; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000235:genetics; D013025:Glycine max / Q000737:chemistry
chemical_list: C113920:EIF4G1 protein, human; D039603:Eukaryotic Initiation Factor-4G; D007529:Isoflavones; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D011960:Receptors, Estrogen; D060754:Equol
keywords: Myc (c-Myc); breast cancer; cancer stem cells; cell growth; equol; eukaryotic translation initiation factor 4G (eIF4G); protein synthesis; soy