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Expression and activity of eIF6 trigger Malignant Pleural Mesothelioma growth in vivo

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journal contribution
posted on 20.06.2016, 13:22 by A. Miluzio, S. Oliveto, E. Pesce, L. Mutti, B. Murer, Stefano Grosso, S. Ricciardi, D. Brina, S. Biffo
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.

Funding

Fondazione BUZZI UNICEM; AIRC IG 2014; AICR UK 13-0045; ERC “translate” 338999.

History

Citation

Oncotarget, Vol. 6, No. 35

Version

VoR (Version of Record)

Published in

Oncotarget

Publisher

Impact Journals

eissn

1949-2553

Acceptance date

24/09/2015

Available date

20/06/2016

Publisher version

http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path[]=5462

Language

en