The Warburg Effect and Glutamine: Targeting the Deregulation of Metabolism in Human Hepatocellular Carcinoma Cells
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Hepatocellular carcinoma (HCC) is the most common type of liver cancer in the world. Effective therapy options are limited; sorafenib is currently the only FDA-approved medication for the disease. In order improve clinical prognoses, alternative treatment options must be assessed and their mechanisms of action elucidated. An important hallmark of cancer is the deregulation of normal cellular energetics, resulting in a number of crucial metabolic adaptations to promote excessive proliferation. These changes include: the upregulation of aerobic glycolysis (the “Warburg Effect”), coordinate over-expression of the tertiary nutrient transporter system ASCT2 and LAT1, and enhanced glutamine uptake to support biosynthesis and stimulate growth signaling. It is important to discover, understand, and exploit the metabolic differences between normal and cancerous hepatocytes in order to develop successful therapies for HCC. This project is comprised of three objectives: (1) to assess the efficacy and effective median dosage of a multitude of metabolic inhibitors on a panel of epithelial and mesenchymal-derived HCC cell lines, (2) to determine the growth impact of depriving SK-Hep-1-derived shRNA-mediated ASCT2 and LAT1 knockdown cell lines of glutamine, and finally (3) to quantify the expression of ASCT2 and LAT1 in cell lines under specific treatment conditions. These objectives were accomplished through the combined usage of cell culture techniques, proliferative assays, and western blot analysis. The most significant results include the effects of metformin, a drug currently prescribed to patients with type 2 diabetes. The efficacy of metformin in vitro was determined to be comparable to the FDA-approved medication sorafenib. Metformin was also found to upregulate ASCT2 expression in both epithelial and mesenchymal cell lines. Assessing the biochemical effects of metformin on HCC is necessary to answer a critical question in cancer biology: how does metformin induce cell death in human hepatocellular carcinoma?