Cargando…
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...
Autores principales: | , , , , , , |
---|---|
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 |
_version_ | 1784755628566118400 |
---|---|
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. |
format | Online Article Text |
id | pubmed-9319760 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT scagliolaalessandra inhibitionofeif6activityreduceshepatocellularcarcinomagrowthaninvivoandinvitrostudy AT miluzioannarita inhibitionofeif6activityreduceshepatocellularcarcinomagrowthaninvivoandinvitrostudy AT morigiada inhibitionofeif6activityreduceshepatocellularcarcinomagrowthaninvivoandinvitrostudy AT ricciardisara inhibitionofeif6activityreduceshepatocellularcarcinomagrowthaninvivoandinvitrostudy AT olivetostefania inhibitionofeif6activityreduceshepatocellularcarcinomagrowthaninvivoandinvitrostudy AT manfrininicola inhibitionofeif6activityreduceshepatocellularcarcinomagrowthaninvivoandinvitrostudy AT biffostefano inhibitionofeif6activityreduceshepatocellularcarcinomagrowthaninvivoandinvitrostudy |