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Inhibition of eIF6 Activity Reduces Hepatocellular Carcinoma Growth: An In Vivo and In Vitro Study

Nonalcoholic fatty liver disease (NAFLD) is characterized by the accumulation of lipids in the liver. Given the high prevalence of NAFLD, its evolution to nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC) is of global concern. Therapies for managing NASH-driven HCC can benefit f...

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Autores principales: Scagliola, Alessandra, Miluzio, Annarita, Mori, Giada, Ricciardi, Sara, Oliveto, Stefania, Manfrini, Nicola, Biffo, Stefano
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9319760/
https://www.ncbi.nlm.nih.gov/pubmed/35887068
http://dx.doi.org/10.3390/ijms23147720
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author Scagliola, Alessandra
Miluzio, Annarita
Mori, Giada
Ricciardi, Sara
Oliveto, Stefania
Manfrini, Nicola
Biffo, Stefano
author_facet Scagliola, Alessandra
Miluzio, Annarita
Mori, Giada
Ricciardi, Sara
Oliveto, Stefania
Manfrini, Nicola
Biffo, Stefano
author_sort Scagliola, Alessandra
collection PubMed
description Nonalcoholic fatty liver disease (NAFLD) is characterized by the accumulation of lipids in the liver. Given the high prevalence of NAFLD, its evolution to nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC) is of global concern. Therapies for managing NASH-driven HCC can benefit from targeting factors that play a continuous role in NAFLD evolution to HCC. Recent work has shown that postprandial liver translation exacerbates lipid accumulation through the activity of a translation factor, eukaryotic initiation factor 6 (eIF6). Here, we test the effect of eIF6 inhibition on the progression of HCC. Mice heterozygous for eIF6 express half the level of eIF6 compared to wt mice and are resistant to the formation of HCC nodules upon exposure to a high fat/high sugar diet combined with liver damage. Histology showed that nodules in eIF6 het mice were smaller with reduced proliferation compared to wt nodules. By using an in vitro model of human HCC, we confirm that eIF6 depletion reduces the growth of HCC spheroids. We also tested three pharmacological inhibitors of eIF6 activity—eIFsixty-1, eIFsixty-4, and eIFsixty-6—and all three reduced eIF6 binding to 60S ribosomes and limited the growth of HCC spheroids. Thus, inhibition of eIF6 activity is feasible and limits HCC formation.
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spelling pubmed-93197602022-07-27 Inhibition of eIF6 Activity Reduces Hepatocellular Carcinoma Growth: An In Vivo and In Vitro Study Scagliola, Alessandra Miluzio, Annarita Mori, Giada Ricciardi, Sara Oliveto, Stefania Manfrini, Nicola Biffo, Stefano Int J Mol Sci Article Nonalcoholic fatty liver disease (NAFLD) is characterized by the accumulation of lipids in the liver. Given the high prevalence of NAFLD, its evolution to nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC) is of global concern. Therapies for managing NASH-driven HCC can benefit from targeting factors that play a continuous role in NAFLD evolution to HCC. Recent work has shown that postprandial liver translation exacerbates lipid accumulation through the activity of a translation factor, eukaryotic initiation factor 6 (eIF6). Here, we test the effect of eIF6 inhibition on the progression of HCC. Mice heterozygous for eIF6 express half the level of eIF6 compared to wt mice and are resistant to the formation of HCC nodules upon exposure to a high fat/high sugar diet combined with liver damage. Histology showed that nodules in eIF6 het mice were smaller with reduced proliferation compared to wt nodules. By using an in vitro model of human HCC, we confirm that eIF6 depletion reduces the growth of HCC spheroids. We also tested three pharmacological inhibitors of eIF6 activity—eIFsixty-1, eIFsixty-4, and eIFsixty-6—and all three reduced eIF6 binding to 60S ribosomes and limited the growth of HCC spheroids. Thus, inhibition of eIF6 activity is feasible and limits HCC formation. MDPI 2022-07-13 /pmc/articles/PMC9319760/ /pubmed/35887068 http://dx.doi.org/10.3390/ijms23147720 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Scagliola, Alessandra
Miluzio, Annarita
Mori, Giada
Ricciardi, Sara
Oliveto, Stefania
Manfrini, Nicola
Biffo, Stefano
Inhibition of eIF6 Activity Reduces Hepatocellular Carcinoma Growth: An In Vivo and In Vitro Study
title Inhibition of eIF6 Activity Reduces Hepatocellular Carcinoma Growth: An In Vivo and In Vitro Study
title_full Inhibition of eIF6 Activity Reduces Hepatocellular Carcinoma Growth: An In Vivo and In Vitro Study
title_fullStr Inhibition of eIF6 Activity Reduces Hepatocellular Carcinoma Growth: An In Vivo and In Vitro Study
title_full_unstemmed Inhibition of eIF6 Activity Reduces Hepatocellular Carcinoma Growth: An In Vivo and In Vitro Study
title_short Inhibition of eIF6 Activity Reduces Hepatocellular Carcinoma Growth: An In Vivo and In Vitro Study
title_sort inhibition of eif6 activity reduces hepatocellular carcinoma growth: an in vivo and in vitro study
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9319760/
https://www.ncbi.nlm.nih.gov/pubmed/35887068
http://dx.doi.org/10.3390/ijms23147720
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