A systems biology approach for the identification of glycolysis key regulators in cancer cells

The Warburg effect, one of the most important hallmarks of cancer, emerges from the observation that cancer cells produce energy mainly by means of glycolysis followed by lactic acid fermentation also in the presence of oxygen. This property of many cancer cells constitutes a weak point that can be exploited to affect their proliferation. We apply a systems biology approach to study the glycolysis and its regulation by a series of proteins (c-Myc, p53, Hif-1 and Akt) which play a relevant role in cancer and in the context of the Warburg effect, in order to identify the key regulators of the glycolytic flux specifically in cancer conditions compared to normal cells. The glycolysis and its regulation mediated by the proteins listed above have been modelled by means of a deterministic and continuous kinetic model. Lactic acid concentrations after glucose starvation have been collected from WT (wild type) and CA-AKT (constitutively active AKT) HEK (Human Embryonic Kidney) 293 cells. The kinetic model reproduces the increased production of lactic acid observed in CA-AKT HEK293 cells (cancer condition) respect to WT-AKT HEK 293 cells (normal condition). Using the Metabolic Control Analysis (MCA) theory the flux control coefficients were calculated both in cancer and normal conditions. Through this analysis we predicted the biochemical processes that exert a high control over the glycolytic flux specifically in cancer conditions. The proteins which regulate the biochemical processes identified by using MCA constitute drug target candidates that can be used, according to our model predictions, to affect the glycolytic flux specifically in cancer conditions. More than one of these key regulators can be contemporaneously targeted in order to obtain the strongest reduction of the glycolytic flux in cancer cells.