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

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. Prostate cancer is the second most frequently diagnosed malignancy in men in the USA 1. Conventional therapies provide a high percentage of the cure for patients with localized prostate cancer, but there is no cure once the disease has spread beyond the prostate and once it fails to respond to androgen deprivation therapies 2. Metastatic castration-resistant prostate cancer (CRPC) is estimated to result in about 26,730 deaths in 2017 in the USA 1. There is an urgent and unmet need for identification and characterization of new molecular targets for efficient diagnosis and development of novel therapeutic options in PCa. Cap-dependent translation is essential to maintain high protein synthesis and translation of specific mRNAs that are responsible for various tumorigenic properties in cancer cells. Translational control occurs predominately during a rate-limiting, initiation step which is subjected to extensive regulation 3,4 and is governed by cap-binding complex, eukaryotic initiation factor 4 F (eIF4F) which comprises cap-binding protein eIF4E, eIF4A (helicase) and eIF4G (scaffolding protein). The eIF4F complex recruits ribosomes to mRNA such that the 5′ untranslated region (5′ UTR) can be scanned by ribosomes in search of an initiation codon 4. An interaction between eIF4G and eIF4E is crucial for the formation of the eIF4F complex and initiation of cap-dependent translation 5. The eIF4G family comprises three isoform eIF4G1, eIF4G2 and eIF4G3 6 among