Cargando…
Oxidative phosphorylation activation is an important characteristic of DOX resistance in hepatocellular carcinoma cells
BACKGROUND: Despite the implications for tumor growth and cancer drug resistance, the mechanisms underlying differences in energy metabolism among cells remain unclear. METHODS: To analyze differences between cell types, cell viability, ATP and α-ketoglutaric acid levels, the oxygen consumption rate...
Autores principales: | , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2018
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5799923/ https://www.ncbi.nlm.nih.gov/pubmed/29402287 http://dx.doi.org/10.1186/s12964-018-0217-2 |
_version_ | 1783298097911169024 |
---|---|
author | Wu, Li Zhao, Jiayu Cao, Kexin Liu, Xiao Cai, Hao Wang, Jiaqi Li, Weidong Chen, Zhipeng |
author_facet | Wu, Li Zhao, Jiayu Cao, Kexin Liu, Xiao Cai, Hao Wang, Jiaqi Li, Weidong Chen, Zhipeng |
author_sort | Wu, Li |
collection | PubMed |
description | BACKGROUND: Despite the implications for tumor growth and cancer drug resistance, the mechanisms underlying differences in energy metabolism among cells remain unclear. METHODS: To analyze differences between cell types, cell viability, ATP and α-ketoglutaric acid levels, the oxygen consumption rate and extracellular acidification rate, and the expression of key enzymes involved in α-KG metabolism and transfer were examined. Additionally, UPLC-MS/MS was used to determine the doxorubicin (DOX) content in SMMC-7721 and SMMC-7721/DOX cells. RESULTS: We found that energy metabolism in SMMC-7721 cells is mainly dependent on the glycolysis pathway, whereas SMMC-7721/DOX cells depend more heavily on the oxidative phosphorylation pathway. Cell viability and intracellular ATP levels in SMMC-7721/DOX cells were significantly reduced by rotenone and oligomycin, inhibitors of oxidative phosphorylation. However, SMMC-7721 cell properties were more strongly influenced by an inhibitor of glycolysis, 2-deoxy-d-glucose. Furthermore, the suppressive effect of α-KG on ATP synthase plays an important role in the low levels of oxidative phosphorylation in SMMC-7721 cells; this effect could be strengthened by the metabolic poison methotrexate and reversed by l-(−)-malic acid, an accelerator of the malate-aspartate cycle. CONCLUSIONS: The inhibitory effect of α-KG on ATP synthase was uncoupled with the tricarboxylic acid cycle and oxidative phosphorylation in SMMC-7721 cells; accordingly, energy metabolism was mainly determined by glycolysis. In drug-resistant cells, a remarkable reduction in the inhibitory effects of α-KG on ATP synthase resulted in better coordination among the TCA cycle, oxidative phosphorylation, and glycolysis, providing novel potential strategies for clinical treatment of liver cancer resistance. |
format | Online Article Text |
id | pubmed-5799923 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-57999232018-02-13 Oxidative phosphorylation activation is an important characteristic of DOX resistance in hepatocellular carcinoma cells Wu, Li Zhao, Jiayu Cao, Kexin Liu, Xiao Cai, Hao Wang, Jiaqi Li, Weidong Chen, Zhipeng Cell Commun Signal Research BACKGROUND: Despite the implications for tumor growth and cancer drug resistance, the mechanisms underlying differences in energy metabolism among cells remain unclear. METHODS: To analyze differences between cell types, cell viability, ATP and α-ketoglutaric acid levels, the oxygen consumption rate and extracellular acidification rate, and the expression of key enzymes involved in α-KG metabolism and transfer were examined. Additionally, UPLC-MS/MS was used to determine the doxorubicin (DOX) content in SMMC-7721 and SMMC-7721/DOX cells. RESULTS: We found that energy metabolism in SMMC-7721 cells is mainly dependent on the glycolysis pathway, whereas SMMC-7721/DOX cells depend more heavily on the oxidative phosphorylation pathway. Cell viability and intracellular ATP levels in SMMC-7721/DOX cells were significantly reduced by rotenone and oligomycin, inhibitors of oxidative phosphorylation. However, SMMC-7721 cell properties were more strongly influenced by an inhibitor of glycolysis, 2-deoxy-d-glucose. Furthermore, the suppressive effect of α-KG on ATP synthase plays an important role in the low levels of oxidative phosphorylation in SMMC-7721 cells; this effect could be strengthened by the metabolic poison methotrexate and reversed by l-(−)-malic acid, an accelerator of the malate-aspartate cycle. CONCLUSIONS: The inhibitory effect of α-KG on ATP synthase was uncoupled with the tricarboxylic acid cycle and oxidative phosphorylation in SMMC-7721 cells; accordingly, energy metabolism was mainly determined by glycolysis. In drug-resistant cells, a remarkable reduction in the inhibitory effects of α-KG on ATP synthase resulted in better coordination among the TCA cycle, oxidative phosphorylation, and glycolysis, providing novel potential strategies for clinical treatment of liver cancer resistance. BioMed Central 2018-02-05 /pmc/articles/PMC5799923/ /pubmed/29402287 http://dx.doi.org/10.1186/s12964-018-0217-2 Text en © The Author(s). 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Wu, Li Zhao, Jiayu Cao, Kexin Liu, Xiao Cai, Hao Wang, Jiaqi Li, Weidong Chen, Zhipeng Oxidative phosphorylation activation is an important characteristic of DOX resistance in hepatocellular carcinoma cells |
title | Oxidative phosphorylation activation is an important characteristic of DOX resistance in hepatocellular carcinoma cells |
title_full | Oxidative phosphorylation activation is an important characteristic of DOX resistance in hepatocellular carcinoma cells |
title_fullStr | Oxidative phosphorylation activation is an important characteristic of DOX resistance in hepatocellular carcinoma cells |
title_full_unstemmed | Oxidative phosphorylation activation is an important characteristic of DOX resistance in hepatocellular carcinoma cells |
title_short | Oxidative phosphorylation activation is an important characteristic of DOX resistance in hepatocellular carcinoma cells |
title_sort | oxidative phosphorylation activation is an important characteristic of dox resistance in hepatocellular carcinoma cells |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5799923/ https://www.ncbi.nlm.nih.gov/pubmed/29402287 http://dx.doi.org/10.1186/s12964-018-0217-2 |
work_keys_str_mv | AT wuli oxidativephosphorylationactivationisanimportantcharacteristicofdoxresistanceinhepatocellularcarcinomacells AT zhaojiayu oxidativephosphorylationactivationisanimportantcharacteristicofdoxresistanceinhepatocellularcarcinomacells AT caokexin oxidativephosphorylationactivationisanimportantcharacteristicofdoxresistanceinhepatocellularcarcinomacells AT liuxiao oxidativephosphorylationactivationisanimportantcharacteristicofdoxresistanceinhepatocellularcarcinomacells AT caihao oxidativephosphorylationactivationisanimportantcharacteristicofdoxresistanceinhepatocellularcarcinomacells AT wangjiaqi oxidativephosphorylationactivationisanimportantcharacteristicofdoxresistanceinhepatocellularcarcinomacells AT liweidong oxidativephosphorylationactivationisanimportantcharacteristicofdoxresistanceinhepatocellularcarcinomacells AT chenzhipeng oxidativephosphorylationactivationisanimportantcharacteristicofdoxresistanceinhepatocellularcarcinomacells |