Metabolic reprogramming induced by DCA enhances cisplatin sensitivity through increasing mitochondrial oxidative stress in cholangiocarcinoma

Frontiers in Pharmacology

Pharmacology

Qiao Li¹  Ge Zheng¹  Hanjiao Qin²  Luyan Shen³ 

[1] Department of Hepatobiliary and Pancreatic Surgery, Second Hospital of Jilin University, Changchun, China;Department of Radiation Oncology, The Second Hospital of Jilin University, Changchun, China;Second Hospital of Jilin University, Changchun, China;Key Laboratory of Pathobiology, Department of Pathophysiology, Ministry of Education, Jilin University, Changchun, China;

关键词: metabolic reprogramming;    redox homeostasis;    autophagy;    DCA;    cisplatin sensitivity;    cholangiocarcinoma;   

DOI  :  10.3389/fphar.2023.1128312

 received in 2022-12-20, accepted in 2023-09-13,  发布年份 2023

来源: Frontiers

【 摘 要 】

Background: Cholangiocarcinoma has obvious primary multidrug resistance and is generally resistant to cisplatin and other chemotherapy drugs and high glycolytic levels may be associated with chemotherapy resistance of cholangiocarcinoma cells. Dichloroacetate (DCA) is a specific inhibitor of PDK, which can promote mitochondrial aerobic oxidation process by activating PDH. In the past few years, there have been an increasing number of studies supporting the action of DCA against cancer, which also provided evidence for targeting metabolism to enhance the efficacy of cholangiocarcinoma chemotherapy.Methods: Glucose uptake and lactic acid secretion were used to detect cell metabolism level. Cell apoptosis and cell cycle were detected to confirm cell fate induced by cisplatin combined with DCA. Mito-TEMPO was used to inhibit mtROS to explore the relationship between oxidative stress and cell cycle arrest induced by DCA under cisplatin stress. Finally, PCR array and autophagy inhibitor CQ were used to explore the potential protective mechanism under cell stress.Results: DCA changed the metabolic model from glycolysis to aerobic oxidation in cholangiocarcinoma cells under cisplatin stress. This metabolic reprogramming increased mitochondrial reactive oxygen species (mtROS) levels, which promoted cell cycle arrest, increased the expression of antioxidant genes and activated autophagy. Inhibition of autophagy further increased the synergistic effect of DCA and cisplatin.Conclusion: DCA increased cisplatin sensitivity in cholangiocarcinoma cells via increasing the mitochondria oxidative stress and cell growth inhibition. Synergistic effects of DCA and CQ were observed in cholangiocarcinoma cells, which further increased the cisplatin sensitivity via both metabolic reprogramming and inhibition of the stress response autophagy.

【 授权许可】

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Copyright © 2023 Qin, Zheng, Li and Shen.