Mitochondrial uncoupling and the disruption of the metabolic network in hepatocellular carcinoma
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Lilia Turcios1, Francesc Marti1, David S. Watt2,3, Lilia M. Kril2,3, Aman Khurana3,5, Fanny Chapelin3,4, Chunming Liu2,3, Joseph B. Zwischenberger1,3, B. Mark Evers3 and Roberto Gedaly1,3
1 Department of Surgery, Transplant Division, College of Medicine, University of Kentucky, Lexington, KY, USA
2 Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY, USA
3 Lucillle Parker Markey Cancer Center, College of Medicine, University of Kentucky, Lexington, KY, USA
4 Department of Biomedical Engineering, College of Medicine, University of Kentucky, Lexington, KY, USA
5 Department of Radiology, College of Medicine, University of Kentucky, Lexington, KY, USA
Keywords: hepatocellular carcinoma; proton uncouplers; Wnt/β-catenin pathway; glutamine metabolism; mitochondria
Received: May 19, 2020 Accepted: June 30, 2020 Published: August 04, 2020
Background: Hepatocellular Carcinoma (HCC) is the third most common cause of cancer related death worldwide. Adequate treatment options for patients with advanced HCC are currently limited.
Materials and Methods: We studied the anti-HCC effect of FH535 and a novel derivative Y3, on proliferation, mitochondrial function and cellular metabolism focusing on the three key substrates, glutamine, glucose, and fatty acids.
Results: FH535 and Y3 disrupted mitochondrial redox control in HCC cells that resulted from uncoupling mechanisms that increased proton leakage and decreased ATP production leading to apoptosis. The uncoupling effects of the sulfonamides in HCC cells were supported by the loss of activity of the methylated analogs. The accumulation of ROS significantly contributed to cell damage after the impaired autophagic machinery. These sulfonamides, FH535 and Y3, targeted glutamine and fatty acid metabolism and caused HCC cell reprograming towards the preferential use of glucose and the glycolytic pathway.
Conclusions: FH535, and Y3, demonstrated potent anti-HCC activity by targeting OXPHOS, increasing dangerous levels of ROS and reducing ATP production. These sulfonamides target glutamine and FA metabolic pathways significantly increasing the cellular dependency on glycolysis.
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