Expression and activity of eIF6 trigger Malignant Pleural Mesothelioma growthin vivo

Abstract

eIF6 is an antiassociation factor that regulates the availability of active 80S. Its activation is driven by the RACK1/PKCβ axis, in a mTORc1 independent manner. We previously described that eIF6 haploinsufficiency causes a striking survival in the Eμ-Myc mouse lymphoma model, with lifespans extended up to 18 months. Here we screen for eIF6 expression in human cancers. We show that Malignant Pleural Mesothelioma tumors (MPM) and a MPM cell line (REN cells) contain high levels of hyperphosphorylated eIF6. Enzastaurin is a PKC beta inhibitor used in clinical trials. We prove that Enzastaurin treatment decreases eIF6 phosphorylation rate, but not eIF6 protein stability. The growth of REN, in vivo, and metastasis are reduced by either Enzastaurin treatment or eIF6 shRNA. Molecular analysis reveals that eIF6 manipulation affects the metabolic status of malignant mesothelioma cells. Less glycolysis and less ATP content are evident in REN cells depleted for eIF6 or treated with Enzastaurin (Anti-Warburg effect). We propose that eIF6 is necessary for malignant mesothelioma growth, in vivo, and can be targeted by kinase inhibitors.

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. 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.…”

“…EIF6 is a translation initiation factor that plays a role in ribosome complex formation and protein synthesis downstream of PI3K/Akt/mTOR signaling pathway. 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. 49 Functional studies on EIF6 suggest its oncogenic activity through increasing cancer cell motility and invasion.…”

Regulation of eIF6 through multisite and sequential phosphorylation by GSK3β

“…Motif-2 is in the disordered region of the C-terminal tail of eIF6 that is predicted to protrude outside the core structure, which would be favorable for regulatory interactions 10,16 . Also, all the predicted sites indicated in motif-2 were previously identified to be modified by phosphorylation in global proteomic studies including those performed under cellular conditions of stress [35][36][37][38][39][40][41] . Furthermore, previous studies did not detect phosphorylated residues in motif-1 of mammalian eIF6 (PhosphoSitePlus).…”

“…Global proteomic and biochemical studies indicate that eIF6 is phosphorylated at multiple sites and majority of these sites are conserved and cluster around the C-terminal tail [35][36][37][38][39][40][41] . However, most of these phosphorylation sites have not been validated in vivo and the identity of the associated kinases have not been clarified.…”

The eukaryotic Initiation Factor 6 (eIF6) regulates ecdysone biosynthesis by modulating translation inDrosophila

“…Despite its ubiquitous role, eIF6 levels in vivo are tightly regulated, showing considerable variability of expression among different tissues 15 . Importantly, high levels of eIF6 or hyperphosphorylated eIF6 are observed in some cancers 16,17 . eIF6 is rate-limiting for tumor onset and progression in mice 18 .…”