Research Papers:

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

Annarita Miluzio _, Stefania Oliveto, Elisa Pesce, Luciano Mutti, Bruno Murer, Stefano Grosso, Sara Ricciardi, Daniela Brina and Stefano Biffo

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Oncotarget. 2015; 6:37471-37485. https://doi.org/10.18632/oncotarget.5462

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Annarita Miluzio1,*, Stefania Oliveto1,2,*, Elisa Pesce1, Luciano Mutti3, Bruno Murer4, Stefano Grosso5, Sara Ricciardi1, Daniela Brina1, Stefano Biffo1,6

1Molecular Histology and Cell Growth Unit, Istituto Nazionale Genetica Molecolare, “Romeo ed Enrica Invernizzi”, Milano, Italy

2Dipartimento di Scienze e Innovazione Tecnologica, University of Eastern Piedmont, Alessandria, Italy

3Biomedicine Institute, The University of Salford, The Crescent, Salford, UK

4Hospital Dall’Angelo, Pathology Unit, Venice, Italy

5Medical Research Council Toxicology Unit, Leicester, UK

6Department of Biosciences, University of Milan, Milan, Italy

*These authors have contributed equally to this work

Correspondence to:

Stefano Biffo, e-mail: [email protected]

Keywords: Malignant Pleural Mesothelioma, eIF6 phosphorylation, anti-association activity, PKCbeta, Enzastaurin

Received: March 18, 2015     Accepted: September 24, 2015     Published: October 06, 2015


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.

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