Cell proliferation is the driving force behind embryogenesis and the development of an organism, being essential to the correct function of organs and adult tissues. However, it is also plays a crucial part on tumor development. It was only during the last ten years that became more clear the relation between the cell signaling pathways stimulated by growth factors and the cell metabolic activity, which needs during cell division to prioritize the biosynthesis and the increasing in biomass. In tumor cells, glutamine consumption increases concomitantly with the increasing on glutaminase activity. At least three glutaminase isoenzymes accomplish the glutamine to glutamate conversion (liver-type glutaminase, kidney-type glutaminase and glutaminase C) but little is known about the tumor specific needs for each one of them. Results obtained in the laboratory where this proposal is inserted indicate that glutaminase C is the mitochondrial isoform, and, among all them, GAC is the most responsive to the activator inorganic phosphate. Further, their mRNA and protein levels are increased by fetal bovine serum and inhibited by an inhibitor of NFkB. When using an antibody specific for the GAC, an interesting band pattern reveals the emergence of a third band particularly present on the more aggressive breast cancer cell line MDA-MB 231 compared to the SKBR3 and Human Mammary Epithelial Cells (HMEC). This band is also present on the prostate cancer cell line DU145 and absent on another prostate cell line, PC-3. PC-3, unlike the others, is PTEN- and presents the PI3K/AKT/mTOR pathway constantly stimulated. Our goal is to understand the signaling pathways that impact on the glutaminase activity of tumor cells. The particular interest is the regulation of glutaminase C mRNA levels, protein and activity by elements of the NFkB and PI3K pathway as well as AMPK, a regulator of cell energy levels.
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