Mammalian cells require receptor-mediated signaling transduction initiated by extracellular growth factors to leave the quiescent state and enter the cell cycle. The onset of cell growth and division introduces a metabolic requirement for sufficient carbon, nitrogen, and free energy to support synthesis of the new proteins, lipids, and nucleic acids needed by a proliferating cell.
Akt hyperactivation is believed to be associated with increased rates of glucose metabolism observed in tumor cells. Akt signaling exerts a direct influence on glycolysis in cancer cells by several mechanisms. Akt has been shown to regulate the localization of the glucose transporter GLUT1 to the plasma membrane and regulate hexokinase expression, activity, and mitochondrial interaction. In addition, Akt may indirectly activate the glycolysis rate-controlling enzyme phosphofructokinase-1 (PFK1) by directly phosphorylating phosphofructokinase-2 (PFK2), which produces the product, fructose-2.6-bisphosphate (Fru-1,6-P2), which is the most potent allosteric activator of PFK1. In support of these findings, the activity of Akt was found to be correlated to the degree of glycolysis in glioblastoma cells, i.e., the higher the Akt activity, the higher the rate of glycolysis.
There is also a strong relationship between EGFR and glucose metabolism. EGFR may additionally influence with glucose metabolism as it has been found that the physical presence of EGFR within the membrane stabilizes the sodium glucose cotransporter (SGLT1) that may cause increased glucose consumption by EGFR over expression independent of EGFR signaling initiation.
The HIF1 (hypoxia inducible factor 1) signaling pathway also plays a central role in the regulation of cellular glucose metabolism.HIF1 is a transcription factor that was initially identified through its role in the adaptive cellular response to hypoxia (low oxygen tension). When oxygen is limited, the rebs cycle in the mitochondriawill cause mitochondrial redox stress if ATP continues to be produced solely by oxidative phosphorylation. Under these conditions, HIF1 promotes the expression of genes whose products are involved in anaerobic glycolysis.This leads to increased generation of ATP in the cytosol from the conversion of glucose to pyruvate.
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• Simons A L, et al. The role of Akt pathway signaling in glucose metabolism and metabolic oxidative stress[M]//Oxidative Stress in Cancer Biology and Therapy. Humana Press, 2012: 21-46.