Pancreatic cancers rely on a novel glutamine metabolism pathway to maintain redox balance

The metabolic requirements of a proliferating cell differ from those of a cell in homeostasis. In order for a cell to duplicate, it must double its genome, protein content and lipid mass. This process requires energy in the form of ATP and NADPH. However, unlike ATP, the amount of NADPH required for biosynthesis is much greater than that needed for homeostasis, which makes the generation of NADPH rate limiting for cellular proliferation. NADPH is used for both macromolecular biosynthesis (e.g., lipids and deoxynucleotide triphosphates) and the maintenance of a reduced intracellular environment. Given this dual role, when the demand for NADPH is high (e.g., during proliferation), moderate impacts on NADPH production challenge the maintenance of redox control. As such, the generation of reducing power in the form of NADPH is tightly regulated during proliferation to ensure that a sufficient amount is available to run biosynthetic reactions and protect against oxidative stress. Recently, we demonstrated that mutant Kras is required for maintenance of established pancreatic tumors, in part through the regulation of anabolic glucose metabolism. Mutant Kras drives glucose uptake and its diversion into the non-oxidative arm of the pentose phosphate pathway (PPP) to generate ribose 5-phosphate, which is used in nucleic acid biosynthesis. This was a particularly surprising finding, as such metabolic rewiring bypasses the NADPH-generating oxidative arm of the PPP and suggests that an alternate mechanism for NADPH production must dominate in Kras-transformed pancreatic tumors. In a recent study, we used an Pancreatic cancers rely on a novel glutamine metabolism pathway to maintain redox balance