FRUCTOSE DIET INDUCES A METABOLIC REPROGRAMMING TO ENHANCE TUMOR AGGRESSIVENESS

Abstract

HCC is one of the main causes of cancer-related death worldwide and has third place in mortality. One of the main risk factors is metabolic-associated fatty liver disease (MAFLD), having hepatic steatosis, and related metabolic disorders. Mexican population has the highest obesity rate in both children and adults, and the consumption of hypercaloric diets has been related to that. Also, Mexico is in the top five countries with a higher fructose-enriched diet consumption and has been proved already the relation between fructose consumption and MAFLD. Likewise, fructose has been related to metabolic rewiring in transformed cells, enhancing aggressiveness and survival. To analyze fructose role on aggressiveness promotion of HCC cells. We used C57Bl/6J mice strain (both sex) with a high Fructose diet (Fru) (33% of fructose in the drinking water, ad libitum ). Fru supplementation started with 15 days-old mice, two days after DEN was injected (10 μg/Kg, i.p), and the treatment was ended 8 months later. The UAM ethics committee approved the protocol. In vitro studies were carried out with the Huh-7 HCC cell line and we evaluated metabolic and biochemical parameters. Tissue samples were analyzed by H&E. We observed that the fructose-enriched diet group mice presented fat accumulation in the hepatocytes and also areas with a greater inflammatory infiltrate (Fru). Mice in the fructose-enriched diet + DEN (Fru/HCC) group showed a marked difference between the tumor area and the surrounding tissue and an increase in the number of bile ducts, indicating liver tissue damage. Also, we analyzed the protein content of some lipogenic enzymes and noticed an increment in fatty acid synthase (Fasn) in Fru and Fru/HCC. Due to that, we analyzed if Fru treatment was inducing metabolic rewiring in transformed cells. We obtained metabolic changes in fructose-treated cells, reducing the glycolytic pathway and the traditional Warburg effect. Then we evaluated if the Huh-7 under a Fru treatment was more dependent on mitochondria or glycolysis ATP generation. We observed a reduction in proliferation under oligomycin treatment vs . 2-DG treatment. At least, we evaluated the pentose phosphate pathway (PPP) under a Fru treatment and obtained a higher glucose-6-phosphate dehydrogenase (G-6-P DH) activity with Fru vs. only glucose (Glc). Also, G-6-P DH had a more efficient activity in the presence of Fru because the time to reach the Vmax is lower vs . Glc. Fructose induces a metabolic rewiring in cancer cells to enhance ATP production, NADPH, and nucleotides to sustain the active lipid synthesis and proliferation. The fructose-enriched diets promote an aberrant lipogenic phenotype enhancing tumor aggressiveness. Conacyt, Froteras de la Ciencia 1320. The authors declare that there is no conflict of interest.