Metabolic reprogramming enables hepatocarcinoma cells to efficiently adapt and survive to a nutrient-restricted microenvironment

Abstract

<p>Hepatocellular carcinoma (HCC) is a metabolically heterogeneous cancer and the use of glucose by HCC cells could impact their tumorigenicity. Dt81Hepa1-6 cells display enhanced tumorigenicity compared to parental Hepa1-6 cells. This increased tumorigenicity could be explained by a metabolic adaptation to more restrictive microenvironments. When cultured at high glucose concentrations, Dt81Hepa1-6 displayed an increased ability to uptake glucose (<i>P</i><0.001), increased expression of 9 glycolytic genes, greater GTP and ATP (<i>P</i><0.001), increased expression of 7 fatty acid synthesis-related genes (<i>P</i><0.01) and higher levels of Acetyl-CoA, Citrate and Malonyl-CoA (<i>P</i><0.05). Under glucose-restricted conditions, Dt81Hepa1-6 used their stored fatty acids with increased expression of fatty acid oxidation-related genes (<i>P</i><0.01), decreased triglyceride content (<i>P</i><0.05) and higher levels of GTP and ATP (<i>P</i><0.01) leading to improved proliferation (<i>P</i><0.05). Inhibition of lactate dehydrogenase and aerobic glycolysis with sodium oxamate led to decreased expression of glycolytic genes, reduced lactate, GTP and ATP levels (<i>P</i><0.01), increased cell doubling time (<i>P</i><0.001) and reduced fatty acid synthesis. When combined with cisplatin, this inhibition led to lower cell viability and proliferation (<i>P</i><0.05). This metabolic-induced tumorigenicity was also reflected in human Huh7 cells by a higher glucose uptake and proliferative capacity compared to HepG2 cells (<i>P</i><0.05). In HCC patients, increased tumoral expression of <i>Glut-1</i>, <i>Hexokinase II</i> and <i>Lactate dehydrogenase</i> correlated with poor survival (<i>P</i> = 2.47E⁻⁵, <i>P</i> = 0.016 and <i>P</i> = 6.58E⁻⁵). In conclusion, HCC tumorigenicity can stem from a metabolic plasticity allowing them to thrive in a broader range of glucose concentrations. In HCC, combining glycolytic inhibitors with conventional chemotherapy could lead to improved treatment efficacy.</p