eIF6 is an antiassociation factor that regulates the availability of active 80S. Its activation is driven by the RACK1/PKC beta axis, in a mTORc1 independent manner. We previously described that eIF6 haploinsufficiency causes a striking survival in the E mu-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.

Expression and activity of eIF6 trigger Malignant Pleural Mesothelioma growth in vivo / A. Miluzio, S. Oliveto, E. Pesce, L. Mutti, B. Murer, S. Grosso, S. Ricciardi, D. Brina, S. Biffo. - In: ONCOTARGET. - ISSN 1949-2553. - 6:35(2015 Nov 10), pp. 37480-37494. [10.18632/oncotarget.5462]

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

A. Miluzio
Primo
;
E. Pesce;S. Ricciardi;S. Biffo
Ultimo
2015

Abstract

eIF6 is an antiassociation factor that regulates the availability of active 80S. Its activation is driven by the RACK1/PKC beta axis, in a mTORc1 independent manner. We previously described that eIF6 haploinsufficiency causes a striking survival in the E mu-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.
Enzastaurin; Malignant Pleural Mesothelioma; PKCbeta; anti-association activity; eIF6 phosphorylation
Settore BIO/06 - Anatomia Comparata e Citologia
10-nov-2015
6-ott-2015
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/337005
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