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

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.

CDK12 phosphorylates 4E-BP1 to enable mTORC1-dependent translation and mitotic genome stability

“…Consequently, CDK12 may phosphorylate 4E-BP1 in the nucleus, and, indeed, could even act cotranscriptionally to remodel 5 ′ cap complex of nascent target mRNAs. Consistent with our findings, previous work has established that eIF4G1 is especially important for cell growth and metastasis of prostate and serous ovarian cancers (Li et al 2016a;Jaiswal et al 2018) and selectively controls the translation of a subset of mRNAs encoding DNA repair and cell survival factors (Badura et al 2012). Moreover, the abnormally elevated levels of eIF4E found in cancer cells were shown to regulate translation of a select set of mRNAs critical for transformation and cancer cell survival, acting through mRNAs with a unique 5 ′ leader sequence (Truitt et al 2016).…”

Prognostic Significance of EIF4G1 in Patients with Pancreatic Ductal Adenocarcinoma<strong> </strong>

“…Increased expression of E1F4G1 has been found in inflammatory breast cancer, lung cancer, hypopharyngeal cancer and nasopharyngeal cancer which are consistent with our findings [11,14]. Also higher expression of EIF4G1 is associated with shorter overall survival in various cancers [11,[13][14][15][16]. EIF4G1 may play a tumorigenic role through enhancing translation of IRES-containing p120 mRNA, which contributed to survival of breast tumor cell [13].…”

Targeting the TLK1/NEK1 DDR axis with Thioridazine suppresses outgrowth of androgen independent prostate tumors

“…( c )–( e ) Nek1 expression and Gene Amplification in PCa samples analyzed as described in Ref. . ( c ) Nek1 mRNA is upregulated and amplified in patients in CRPC‐Neuroendocrine Prostate Cancer dataset.…”