Cell communication and signaling : CCS · 2018
Oxidative phosphorylation activation is an important characteristic of DOX resistance in hepatocellular carcinoma cells.
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Wu Li, Zhao Jiayu, Cao Kexin, Liu Xiao, Cai Hao, Wang Jiaqi, Li Weidong, Chen Zhipeng
Аннотация
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.
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.