Metabolic reprogramming induced by fructose promotes therapy´s failure in liver cancer cells in vitro and in vivo.

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Metabolic reprogramming is a hallmark of cancer cells. Fructose metabolism is decreased in liver cancer cells to counteract the oxidative environment induced by fructose. Ketohexokinase (KHK) A is overexpressed, and its switch confers advantages to cancer cells. The objective was to investigate the effect of fructose metabolism on the aggressiveness of liver cancer cells. KHK isoform expression was measured by qRT-PCR in Huh-7 and HepG2 cells. Metabolic characteristics of liver cancer cells (Huh-7 and HepG2) treated with a fructose (1mM) for 48h in a high glucose DMEM media (11mM) was developed using Mito Fuel Flex assay and Glycolysis Rate Assay using SeaHorse technology. To prove the hypothesis that fructose metabolism enhances aggressiveness, we performed proliferation and enzymatic assays. Chemoresistance assays ( in vitro and in vivo ) was developed using Huh-7 cells previously treated with Fructose (1mM) for 72h. Then, we applied Fructose (1mM), Cisplatin (CDDP, 22,11µM for in vitro assays or 100µM for in vivo assays) or Fructose (1mM) + CDDP (22,11µM for in vitro or 100µM for in vivo) for 48h. Huh-7 cells expressed higher levels of khk-a compared to HepG2 cells. The isoform switch was associated with improved fructose uptake and higher proliferation in Huh-7 cells. We did not detect differences in mitochondrial glucose or fatty acid oxidation capacity, but glutamine oxidation capacity was lower in Huh-7, indicating the overall dependence of this cell line on the glutamine pathway. However, we only detected differences with fructose-treated (Fru-treated) cells with less dependence on fatty acid oxidation in hepatoma cells, suggesting that fructose metabolism has a different effect with respect to the differentiation level of the cells. Next, we evaluated the glycolytic pathway in the aggressive cell line (Huh-7), and the analysis showed that Fru-treated cells contributed less to media acidification, suggesting the activation of alternative pathways by fructose. The pentose phosphate pathway was affected by fructose and inhibition of glutathione reductase abolished the benefits gained. We then assessed survival to CDDP treatment, and found that both, in vitro and in vivo, fructose treatment improved survival and resistance to CDDP therapy. Fructose promotes a metabolic remodeling leading to the sustained proliferation of liver cancer cells. Specifically, fructose metabolism promotes alternative metabolic pathways that contribute to the aggressiveness of HCC cells. In addition, fructose may increase cancer cell survival and the treatment failure.

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