Eukaryotic Translation Initiation Factor 4 Gamma 1 (eIF4G1) is upregulated during Prostate cancer progression and modulates cell growth and metastasis

Abstract

Abstract eIF4G1, a critical component of the eIF4F complex, is required for cap-dependent mRNA translation, a process necessary for tumor growth and survival. However, the role of eIF4G1 has not been evaluated in Prostate Cancer (PCa). We observed an increased eIF4G1 protein levels in PCa tissues as compared to normal tissues. Analysis of the TCGA data revealed that eIF4G1 gene expression positively correlated with higher tumor grade and stage. Furthermore, eIF4G1 was over-expressed and or amplified, in 16% patients with metastatic PCa (SU2C/PCF Dream Team dataset) and in 59% of castration-resistant prostate cancer (CRPC) patients (Trento/Cornell/Broad dataset). We showed for the first time that eIF4G1 expression was increased in PCa and that increased eIF4G1 expression associated with tumor progression and metastasis. We also observed high protein levels of eIF4G1 in PCa cell lines and prostate tissues from the TRAMP model of PCa as compared to normal prostate cell line and prostate tissues from the wild type mice. Knockdown of eIF4G1 in PCa cells resulted in decreased Cyclin D1 and p-Rb protein level, cell cycle delay, reduced cell viability and proliferation, impaired clonogenic activity, reduced cell migration and decreased mRNA loading to polysomes. Treatment with eIF4G complex inhibitor also impaired prostasphere formation. eIF4G1 knockdown or treatment with eIF4G complex inhibitor sensitized CRPC cells to Enzalutamide and Bicalutamide. Our results showed that eIF4G1 plays an important role in PCa growth and therapeutic resistance. These data suggested that eIF4G1 functions as an oncoprotein and may serve as a novel target for intervention in PCa and CRPC.