Expression and activity of eIF6 trigger malignant pleural mesothelioma growth in vivo

Our plain-English summary of Expression and activity of eIF6 trigger malignant pleural mesothelioma growth in vivo, by A. Miluzio, S. Oliveto, E. Pesce, et al (Oncotarget, 2015).

The study

• Authors: A. Miluzio, S. Oliveto, E. Pesce, L. Mutti, B. Murer, S. Grosso, S. Ricciardi, D. Brina, S. Biffo
• Journal: Oncotarget
• Published: 2015;6(35):37471-85
• Cited by: 35 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This was a laboratory study of malignant pleural mesothelioma. It did not study asbestos exposure. It looked at eIF6, a protein that helps cells make proteins. The authors stained 24 human tumor samples from an Italian cohort and found high eIF6 levels in all of them. In a public gene dataset, 35 of 42 patients had higher eIF6 mRNA in tumor samples. No relationship was seen between eIF6 mRNA levels and survival, but high combined eIF6 and PKC beta gene expression was linked to lower survival. The REN mesothelioma cell line had more eIF6, and more of its activated form, than non-tumor mesothelial cells. Lowering eIF6, or giving the drug Enzastaurin, slightly slowed growth of cultured cells. It also reduced lactate secretion, which the authors treated as a measure of glycolysis (sugar breakdown), and lowered cellular ATP. In immunodeficient mice injected with REN cells, both approaches reduced tumor weight and spread to the diaphragm. The authors suggested that eIF6 could be a treatment target. They cautioned that Enzastaurin may not block eIF6 effectively in the long run, because eIF6 has multiple poorly characterized phosphorylation sites.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study combining staining of human tumor samples, analysis of a public gene-expression dataset, cell culture experiments, and a mouse tumor (xenograft) experiment
• Who was studied: 24 human malignant pleural mesothelioma samples from an Italian cohort (19 epithelial, 3 sarcomatous, 2 biphasic). Also: tumor samples from Glenfield Hospital, Leicester, UK; a public microarray dataset of 54 patients (42 with survival follow-up); mesothelioma cell lines REN, MM98 and MSTO-211H; non-tumorigenic Met-5A mesothelial cells; and NOD-SCID mice (control n = 3, other groups n = 7 each). No dates were given.
• Exposure: No asbestos exposure was studied. The interventions were lowering eIF6 with shRNA and giving the PKC beta inhibitor Enzastaurin: 1, 5 and 10 μM in cultured cells, and 75 mg/kg by gavage twice daily in mice, from day 7 after injection for 5 weeks.
• Main results:
  • In all analyzed human mesothelioma samples, eIF6 was expressed at high levels in the nucleoli and cytoplasm of tumor cells.
  • In the public dataset, 35 of 42 patients had higher eIF6 mRNA in tumor samples.
  • No relationship was observed between eIF6 mRNA levels at the time of analysis and patient survival.
  • High combined eIF6 and PKC beta (PRKCB) gene expression was associated with lower survival (p of 0.005 or less).
  • REN mesothelioma cells showed more eIF6 expression and phosphorylation than non-tumorigenic Met-5A cells.
  • In cultured REN cells, both eIF6 shRNA and Enzastaurin slightly reduced proliferation.
  • In cultured cells, the percentage of cell death was similar across all conditions tested.
  • In mice, REN cells depleted of eIF6 produced lower tumor mass weight and less metastasis, judged by reduced diaphragm weight.
  • In mice given Enzastaurin, tumor mass was strongly reduced, metastasis was limited to the diaphragm, and hemorrhage was mild.
  • In REN cells, eIF6 depletion and Enzastaurin reduced lactate secretion, which the authors call an index of glycolytic flux.
  • In REN cells, ATP production was significantly reduced with both eIF6 depletion and Enzastaurin.
• The authors' conclusion: The authors suggested that changing eIF6 levels and activity may offer a route for tumor therapy, especially where rapalog drugs do not work, as in malignant mesothelioma.
• Limitations the authors state:
  • Inhibition of eIF6 by Enzastaurin may not be effective in the long run, because eIF6 has multiple poorly characterized phosphorylation sites.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Clinical Trial, Metastasis, Mesothelioma.

Related studies

• In Vitro and In Vivo Antitumor Activity of [Pt(O,O'-acac)(γ-acac)(DMS)] in Malignant Pleural Mesothelioma — A. Muscella, C. Vetrugno, et al. (2016)
• Inhibition of ZL55 cell proliferation by ADP via PKC-dependent signalling pathway — A. Muscella, L.G. Cossa, et al. (2018)
• Antagonizing the Hedgehog Pathway with Vismodegib Impairs Malignant Pleural Mesothelioma Growth In Vivo by Affecting Stroma — M. Meerang, K. Bérard, et al. (2016)
• In vitro and in vivo therapeutic efficacy of the PPAR-γ agonist troglitazone in combination with cisplatin against malignant pleural mesothelioma cell growth — N. Hamaguchi, H. Hamada, et al. (2010)
• Merlin deficiency predicts FAK inhibitor sensitivity: a synthetic lethal relationship — I.M. Shapiro, V.N. Kolev, et al. (2014)
• Inhibition of autophagy potentiates pemetrexed and simvastatin-induced apoptotic cell death in malignant mesothelioma and non-small cell lung cancer cells — K.E. Hwang, Y.S. Kim, et al. (2015)

Browse more research in Oncotarget, or return to medical research.