RESUMEN
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.
Asunto(s)
Neoplasias de la Mama/metabolismo , Equol/efectos adversos , Factor 4G Eucariótico de Iniciación/biosíntesis , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Glycine max/química , Fitoestrógenos/efectos adversos , Biosíntesis de Proteínas/efectos de los fármacos , Animales , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Línea Celular Tumoral , Suplementos Dietéticos/efectos adversos , Equol/química , Equol/farmacología , Factor 4E Eucariótico de Iniciación/biosíntesis , Factor 4E Eucariótico de Iniciación/genética , Factor 4G Eucariótico de Iniciación/genética , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Isoflavonas/efectos adversos , Isoflavonas/farmacología , Ratones , Ratones Desnudos , Trasplante de Neoplasias , Fitoestrógenos/química , Fitoestrógenos/farmacología , Biosíntesis de Proteínas/genética , Proteínas Proto-Oncogénicas c-myc/biosíntesis , Proteínas Proto-Oncogénicas c-myc/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , ARN Neoplásico/genética , ARN Neoplásico/metabolismo , Trasplante Heterólogo , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/genéticaRESUMEN
OBJECTIVE: To investigate the activity of Caspase-3 and the expression of eukaryotic initiation factor families, bFGF and VEGF after elemene on laryngeal carcinoma HEp-2 cells. METHOD: The HEp-2 cells after elemene treatment were analyzed utilizing Westernblot and reverse transcriptase polymerase chain reaction (RT-PCR). The activity of Caspase-3 was assessed by colorimetric assay. RESULT: The activity of Caspase-3 was enhanced after elemene treatment. The protein expression of eIF4E, eIF4G, bFGF and VEGF were significantly inhibited by elemene; and the mRNA expression of bFGF and VEGF were inhibited either. CONCLUSION: Elemene can effectively inhibit the growth of HEp-2 cells and result in the alteration of activity of Caspase-3. There were significant correlations between the decreased expression of protein eIF4E, eIF4G, bFGF and VEGF. The mechanism of eIF4E and eIF4G decrease the expression of bFGF and VEGF is post-transcriptional.