eIF6 over-expression increases the motility and invasiveness of cancer cells by modulating the expression of a critical subset of membrane-bound proteins

Abstract

BackgroundEukaryotic Initiation factor 6 (eIF6) is a peculiar translation initiation factor that binds to the large 60S ribosomal subunits, controlling translation initiation and participating in ribosome biogenesis. In the past, knowledge about the mechanisms adopted by the cells for controlling protein synthesis by extracellular stimuli has focused on two translation initiation factors (eIF4E and eIF2), however, recent data suggest eIF6 as a newcomer in the control of downstream of signal transduction pathways. eIF6 is over-expressed in tumors and its decreased expression renders cells less prone to tumor growth. A previous work from our laboratory has disclosed that over-expression of eIF6 in transformed cell lines markedly increased cell migration and invasion.MethodsHere, we performed a quantitative proteomic analysis of membrane-associated proteins in A2780 ovarian cancer cells over-expressing eIF6. Differentially expressed proteins upon eIF6 overproduction were further investigated in silico by Ingenuity Pathway Analysis (IPA). RT-qPCR and Western blot were performed in order to validate the proteomic data. Furthermore, the effects of a potent and selective inhibitor ML-141 in A2780 cells were evaluated using transwell migration assay. Finally, we explored the effects of eIF6 over-expression on WM793 primary melanoma cell lines.ResultsWe demonstrated that: (i) the genes up-regulated upon eIF6 overproduction mapped to a functional network corresponding to cellular movements in a highly significant way; (ii) cdc42 plays a pivotal role as an effector of enhanced migratory phenotype induced upon eIF6 over-expression; (iii) the variations in abundance observed for cdc42 protein occur at a post-transcriptional level; (iv) the increased cell migration/invasion upon eIF6 over-expression was generalizable to other cell line models.ConclusionsCollectively, our data confirm and further extend the role of eIF6 in enhancing cell migration/invasion. We show that a number of membrane-associated proteins indeed vary in abundance upon eIF6 over-expression, and that the up-regulated proteins can be located within a functional network controlling cell motility and tumor metastasis. Full understanding of the role eIF6 plays in the metastatic process is important, also in view of the fact that this factor is a potentially druggable target to be exploited for new anti-cancer therapies.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1106-3) contains supplementary material, which is available to authorized users.

Molecular characterization of colorectal adenomas reveals POFUT1 as a candidate driver of tumor progression

“…45,46 It is overexpressed in multiple tumor types, 47,48 including CRC, where expression of EIF6 has been shown to increase from normal colon, through adenoma to CRC. 50,51 The fact that we identified significant enrichment of PI3K/Akt/mTOR signaling in HRAs when compared to LRAs, suggests that EIF6 and PI3K/Akt/mTOR signaling play a role in adenoma-to-carcinoma progression. 50,51 The fact that we identified significant enrichment of PI3K/Akt/mTOR signaling in HRAs when compared to LRAs, suggests that EIF6 and PI3K/Akt/mTOR signaling play a role in adenoma-to-carcinoma progression.…”

“…49 Functional studies on EIF6 suggest its oncogenic activity through increasing cancer cell motility and invasion. 50,51 The fact that we identified significant enrichment of PI3K/Akt/mTOR signaling in HRAs when compared to LRAs, suggests that EIF6 and PI3K/Akt/mTOR signaling play a role in adenoma-to-carcinoma progression. Additionally, the transcription of EIF6 has been shown to be regulated by NOTCH1, 51 consistent with Notch signaling enrichment in HRAs and CRCs.…”

Hepatic Transcriptome Perturbations in Dairy Cows Fed Different Forage Resources

“…EIF6 is eukaryotic translation initiation factor. Depletion of eIF6 (using specific siRNA-mediated knockdown) in Mz-ChA-2 and TFK-1 cell lines inhibit cell proliferation and induced apoptosis [50], while EIF6 over-expression increases the motility and invasiveness of cancer cells [51]. However, in this study, "positive regulation of apoptotic process" was significantly enriched by downregulated DEG implying that apoptosis was not induced by low-quality forage diet (Fig.…”

The role of eukaryotic translation initiation factor 6 in tumors

“…This effect is particularly notable in Cdc42 (11), a small GTPase belonging to the Ras homolog family (67–69). A number of studies have established that Cdc42 regulates cell differentiation, cell cycle progression, cell polarity, cell fate determination, and cell motility and adhesion (68,70).…”