Abstract 3215: Metabolic alterations of cancer cell as potential anti-cancer target
Authors: Murad H. Al-Salamat
Journal: Cancer Research (2012)

Abstract In cancer cells, energy generating pathways are markedly altered like many other processes. Warburg described this effect as increase the rate of glycolysis in the expense of oxidative phosphorylation. Dysfunctional Mitochondria, not Oxygen insufficiency, cause cancer cells to produce inordinate amounts of Lactic acid. The fact that most cancers have poor vascular systems has led to assume that such cells are deprived of a normal supply of oxygen, and thus it was forced to switch for anaerobic glycolysis. Recently many experiments illustrated that, cancer cells keep using anaerobic glycolysis even under conditions where Oxygen is plentiful, resulting in high rates of lactate formation. This indicates; cancer cell switches to anaerobic glycolysis because it's in need for Lactic acid. In comparison to Morula's cell has higher concentration of Lactic acid, than other fully differentiated adult cells, at the same time it has less concentration than cancer cells. This means that Lactic acid is associated with poor differentiation and high proliferation of cells in both cancer and health situations. But after the cell has been specialized and became fully differentiated, Lactic acid starts losing this property. In this context, Lactic acid playing a pivotal role in cell transformation and p53 de-activation, at the same time it's interfere with signaling pathway to activate or enhance the activity of ERK 1/2, result in cell proliferation. Since there is direct link between p53 and COX by showing p53 induction correlated with an up regulation of COXI subunit expression at the mRNA level. So loss of p53 resulted in decreased COXII protein expression with concomitant decreases in COX enzyme activity, and thus halts Mitochondrial oxidative phosphorylation, at the same time force cells to become entirely dependent on glycolysis to meet energy demands. In response, cells start importing more Glucose into the Cytosol by increase the activity of GLUT, which it's under the control of Atypical PKC isozymes, these isozymes control insulin-stimulated glucose transport by promoting the translocation of glucose transporters to the plasma membrane. PKC isozymes are involved in a wide array of diverse cellular functions. Most isozymes (PKC-beta) are involved in proliferation, and differentiation, whereas (PKC-epsilon) is anti-apoptotic. PKC results in activation of Ras, this in turn results in activation of ERK 1/2, and PI3K. PI3K responsible for activation of MDM2, which results in inhibition p53 activity. And thus, over activation of PKC by Lactic acid results in halting p53, and enhancing the activity of Ras. So obviously Lactic acid has binding site in PKC's domain to activate it. But the difference in its activation in cancer and normal ES cells is that in ES cells is controlled by the amount of Lactic acid produced. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3215. doi:1538-7445.AM2012-3215