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Sorafenib-Induced Autophagy Promotes Glycolysis by Upregulating the p62/HDAC6/HSP90 Axis in Hepatocellular Carcinoma Cells
Sorafenib has attracted much attention as the first drug approved by the FDA for the treatment of advanced hepatocellular carcinoma (HCC). Because of the drug tolerance, the overall outcomes were far from satisfactory. Current studies suggest that changes in glucose metabolism induced by sorafenib a...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2022
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8888828/ https://www.ncbi.nlm.nih.gov/pubmed/35250553 http://dx.doi.org/10.3389/fphar.2021.788667 |
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author | Yan, Xiaoyu Tian, Rui Sun, Jicheng Zhao, Yuanxin Liu, Buhan Su, Jing Li, Minghua Sun, Wei Xu, Xuesong |
author_facet | Yan, Xiaoyu Tian, Rui Sun, Jicheng Zhao, Yuanxin Liu, Buhan Su, Jing Li, Minghua Sun, Wei Xu, Xuesong |
author_sort | Yan, Xiaoyu |
collection | PubMed |
description | Sorafenib has attracted much attention as the first drug approved by the FDA for the treatment of advanced hepatocellular carcinoma (HCC). Because of the drug tolerance, the overall outcomes were far from satisfactory. Current studies suggest that changes in glucose metabolism induced by sorafenib are the pivotal resistant mechanism of HCC cells, but the specific regulatory mechanism remains unclear, which makes it difficult to increase drug sensitivity by targeting glycolysis. As a metabolic-recycling pathway, autophagy regulates multiple important pathways involved in cell survival and death. In this study, we found the expression of key autophagy proteins were closely related to the prognosis and progression of HCC patients. Based on in vitro experiments, our studies showed sorafenib induced autophagy in HCC cells. Inhibition of autophagy by chloroquine could significantly increase the sensitivity of HCC cells to sorafenib and reverse the enhancement of glycolysis. Furthermore, sorafenib-induced autophagy promoted the deacetylase activity of HDAC6 by degrading p62, which promoted the activity of PKM2 by regulating the acetylation of its critical substrate HSP90. In this study, we investigated the role of autophagy-induced HDAC6 in regulating the key glycolytic enzyme PKM2, which may be helpful to clarify the relationship between autophagy and glycolysis in a sorafenib-resistant mechanism. Targeting p62/HDAC6/HSP90 could herald a potential improvement in HCC therapy. |
format | Online Article Text |
id | pubmed-8888828 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-88888282022-03-03 Sorafenib-Induced Autophagy Promotes Glycolysis by Upregulating the p62/HDAC6/HSP90 Axis in Hepatocellular Carcinoma Cells Yan, Xiaoyu Tian, Rui Sun, Jicheng Zhao, Yuanxin Liu, Buhan Su, Jing Li, Minghua Sun, Wei Xu, Xuesong Front Pharmacol Pharmacology Sorafenib has attracted much attention as the first drug approved by the FDA for the treatment of advanced hepatocellular carcinoma (HCC). Because of the drug tolerance, the overall outcomes were far from satisfactory. Current studies suggest that changes in glucose metabolism induced by sorafenib are the pivotal resistant mechanism of HCC cells, but the specific regulatory mechanism remains unclear, which makes it difficult to increase drug sensitivity by targeting glycolysis. As a metabolic-recycling pathway, autophagy regulates multiple important pathways involved in cell survival and death. In this study, we found the expression of key autophagy proteins were closely related to the prognosis and progression of HCC patients. Based on in vitro experiments, our studies showed sorafenib induced autophagy in HCC cells. Inhibition of autophagy by chloroquine could significantly increase the sensitivity of HCC cells to sorafenib and reverse the enhancement of glycolysis. Furthermore, sorafenib-induced autophagy promoted the deacetylase activity of HDAC6 by degrading p62, which promoted the activity of PKM2 by regulating the acetylation of its critical substrate HSP90. In this study, we investigated the role of autophagy-induced HDAC6 in regulating the key glycolytic enzyme PKM2, which may be helpful to clarify the relationship between autophagy and glycolysis in a sorafenib-resistant mechanism. Targeting p62/HDAC6/HSP90 could herald a potential improvement in HCC therapy. Frontiers Media S.A. 2022-02-16 /pmc/articles/PMC8888828/ /pubmed/35250553 http://dx.doi.org/10.3389/fphar.2021.788667 Text en Copyright © 2022 Yan, Tian, Sun, Zhao, Liu, Su, Li, Sun and Xu. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Pharmacology Yan, Xiaoyu Tian, Rui Sun, Jicheng Zhao, Yuanxin Liu, Buhan Su, Jing Li, Minghua Sun, Wei Xu, Xuesong Sorafenib-Induced Autophagy Promotes Glycolysis by Upregulating the p62/HDAC6/HSP90 Axis in Hepatocellular Carcinoma Cells |
title | Sorafenib-Induced Autophagy Promotes Glycolysis by Upregulating the p62/HDAC6/HSP90 Axis in Hepatocellular Carcinoma Cells |
title_full | Sorafenib-Induced Autophagy Promotes Glycolysis by Upregulating the p62/HDAC6/HSP90 Axis in Hepatocellular Carcinoma Cells |
title_fullStr | Sorafenib-Induced Autophagy Promotes Glycolysis by Upregulating the p62/HDAC6/HSP90 Axis in Hepatocellular Carcinoma Cells |
title_full_unstemmed | Sorafenib-Induced Autophagy Promotes Glycolysis by Upregulating the p62/HDAC6/HSP90 Axis in Hepatocellular Carcinoma Cells |
title_short | Sorafenib-Induced Autophagy Promotes Glycolysis by Upregulating the p62/HDAC6/HSP90 Axis in Hepatocellular Carcinoma Cells |
title_sort | sorafenib-induced autophagy promotes glycolysis by upregulating the p62/hdac6/hsp90 axis in hepatocellular carcinoma cells |
topic | Pharmacology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8888828/ https://www.ncbi.nlm.nih.gov/pubmed/35250553 http://dx.doi.org/10.3389/fphar.2021.788667 |
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