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AMPK-Mediated Metabolic Switching Is High Effective for Phytochemical Levo-Tetrahydropalmatine (l-THP) to Reduce Hepatocellular Carcinoma Tumor Growth

Targeting cancer cell metabolism has been an attractive approach for cancer treatment. However, the role of metabolic alternation in cancer is still unknown whether it functions as a tumor promoter or suppressor. Applying the cancer gene-metabolism integrative network model, we predict adenosine mon...

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Autores principales: Yin, Xunzhe, Li, Wenbo, Zhang, Jiaxin, Zhao, Wenjing, Cai, Huaxing, Zhang, Chi, Liu, Zuojia, Guo, Yan, Wang, Jin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8703446/
https://www.ncbi.nlm.nih.gov/pubmed/34940569
http://dx.doi.org/10.3390/metabo11120811
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author Yin, Xunzhe
Li, Wenbo
Zhang, Jiaxin
Zhao, Wenjing
Cai, Huaxing
Zhang, Chi
Liu, Zuojia
Guo, Yan
Wang, Jin
author_facet Yin, Xunzhe
Li, Wenbo
Zhang, Jiaxin
Zhao, Wenjing
Cai, Huaxing
Zhang, Chi
Liu, Zuojia
Guo, Yan
Wang, Jin
author_sort Yin, Xunzhe
collection PubMed
description Targeting cancer cell metabolism has been an attractive approach for cancer treatment. However, the role of metabolic alternation in cancer is still unknown whether it functions as a tumor promoter or suppressor. Applying the cancer gene-metabolism integrative network model, we predict adenosine monophosphate-activated protein kinase (AMPK) to function as a central hub of metabolic landscape switching in specific liver cancer subtypes. For the first time, we demonstrate that the phytochemical levo-tetrahydropalmatine (l-THP), a Corydalis yanhusuo-derived clinical drug, as an AMPK activator via autophagy-mediated metabolic switching could kill the hepatocellular carcinoma HepG2 cells. Mechanistically, l-THP promotes the autophagic response by activating the AMPK-mTOR-ULK1 and the ROS-JNK-ATG cascades and impairing the ERK/AKT signaling. All these processes ultimately synergize to induce the decreased mitochondrial oxidative phosphorylation (OXPHOS) and mitochondrial damage. Notably, silencing AMPK significantly inhibits the autophagic flux and recovers the decreased OXPHOS metabolism, which results in HepG2 resistance to l-THP treatment. More importantly, l-THP potently reduces the growth of xenograft HepG2 tumor in nude mice without affecting other organs. From this perspective, our findings support the conclusion that metabolic change is an alternative approach to influence the development of HCC.
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spelling pubmed-87034462021-12-25 AMPK-Mediated Metabolic Switching Is High Effective for Phytochemical Levo-Tetrahydropalmatine (l-THP) to Reduce Hepatocellular Carcinoma Tumor Growth Yin, Xunzhe Li, Wenbo Zhang, Jiaxin Zhao, Wenjing Cai, Huaxing Zhang, Chi Liu, Zuojia Guo, Yan Wang, Jin Metabolites Article Targeting cancer cell metabolism has been an attractive approach for cancer treatment. However, the role of metabolic alternation in cancer is still unknown whether it functions as a tumor promoter or suppressor. Applying the cancer gene-metabolism integrative network model, we predict adenosine monophosphate-activated protein kinase (AMPK) to function as a central hub of metabolic landscape switching in specific liver cancer subtypes. For the first time, we demonstrate that the phytochemical levo-tetrahydropalmatine (l-THP), a Corydalis yanhusuo-derived clinical drug, as an AMPK activator via autophagy-mediated metabolic switching could kill the hepatocellular carcinoma HepG2 cells. Mechanistically, l-THP promotes the autophagic response by activating the AMPK-mTOR-ULK1 and the ROS-JNK-ATG cascades and impairing the ERK/AKT signaling. All these processes ultimately synergize to induce the decreased mitochondrial oxidative phosphorylation (OXPHOS) and mitochondrial damage. Notably, silencing AMPK significantly inhibits the autophagic flux and recovers the decreased OXPHOS metabolism, which results in HepG2 resistance to l-THP treatment. More importantly, l-THP potently reduces the growth of xenograft HepG2 tumor in nude mice without affecting other organs. From this perspective, our findings support the conclusion that metabolic change is an alternative approach to influence the development of HCC. MDPI 2021-11-29 /pmc/articles/PMC8703446/ /pubmed/34940569 http://dx.doi.org/10.3390/metabo11120811 Text en © 2021 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
Yin, Xunzhe
Li, Wenbo
Zhang, Jiaxin
Zhao, Wenjing
Cai, Huaxing
Zhang, Chi
Liu, Zuojia
Guo, Yan
Wang, Jin
AMPK-Mediated Metabolic Switching Is High Effective for Phytochemical Levo-Tetrahydropalmatine (l-THP) to Reduce Hepatocellular Carcinoma Tumor Growth
title AMPK-Mediated Metabolic Switching Is High Effective for Phytochemical Levo-Tetrahydropalmatine (l-THP) to Reduce Hepatocellular Carcinoma Tumor Growth
title_full AMPK-Mediated Metabolic Switching Is High Effective for Phytochemical Levo-Tetrahydropalmatine (l-THP) to Reduce Hepatocellular Carcinoma Tumor Growth
title_fullStr AMPK-Mediated Metabolic Switching Is High Effective for Phytochemical Levo-Tetrahydropalmatine (l-THP) to Reduce Hepatocellular Carcinoma Tumor Growth
title_full_unstemmed AMPK-Mediated Metabolic Switching Is High Effective for Phytochemical Levo-Tetrahydropalmatine (l-THP) to Reduce Hepatocellular Carcinoma Tumor Growth
title_short AMPK-Mediated Metabolic Switching Is High Effective for Phytochemical Levo-Tetrahydropalmatine (l-THP) to Reduce Hepatocellular Carcinoma Tumor Growth
title_sort ampk-mediated metabolic switching is high effective for phytochemical levo-tetrahydropalmatine (l-thp) to reduce hepatocellular carcinoma tumor growth
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8703446/
https://www.ncbi.nlm.nih.gov/pubmed/34940569
http://dx.doi.org/10.3390/metabo11120811
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