Phosphoglycerate dehydrogenase (PHGDH) catalyzes the committed step in de novo serine biosynthesis. Paradoxically, PHGDH and serine synthesis are required in the presence of abundant environmental serine even when serine uptake exceeds the requirements for nucleotide synthesis. Here, we establish a mechanism for how PHGDH maintains nucleotide metabolism. We show that inhibition of PHGDH induces alterations in nucleotide metabolism independent of serine utilization. These changes are not attributable to defects in serine-derived nucleotide synthesis and redox maintenance, another key aspect of serine metabolism, but result from disruption of mass balance within central carbon metabolism. Mechanistically, this leads to simultaneous alterations in both the pentose phosphate pathway and the tri-carboxylic acid cycle, as we demonstrate based on a quantitative model. These findings define a mechanism whereby disruption of one metabolic pathway induces toxicity by simultaneously affecting the activity of multiple related pathways.
Malignant cells remodel their metabolism to meet the demands of uncontrolled cell proliferation. These demands lead to differential requirements in energy, biosynthetic precursors, and signaling intermediates. Both genetic programs arising from oncogenic events and transcriptional programs and epigenomic events are important in providing the necessary metabolic network activity. Accumulating evidence has established that environmental factors play a major role in shaping cancer cell metabolism. For metabolism, diet and nutrition are the major environmental aspects and have emerged as key components in determining cancer cell metabolism. In this review, we discuss these emerging concepts in cancer metabolism and how diet and nutrition influence cancer cell metabolism.
Altered glucose metabolism is common in cancer. In this issue of Cancer Cell, Morita et al. report new mouse models that express specific isoforms of pyruvate kinase to study glycolysis in tumors. They report several unanticipated findings that challenge current ideas in cancer metabolism.
Edited by Jeffrey E. PessinAerobic glycolysis or the Warburg effect (WE) is characterized by increased glucose uptake and incomplete oxidation to lactate. Although the WE is ubiquitous, its biological role remains controversial, and whether glucose metabolism is functionally different during fully oxidative glycolysis or during the WE is unknown. To investigate this question, here we evolved resistance to koningic acid (KA), a natural product that specifically inhibits glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a rate-controlling glycolytic enzyme, during the WE. We found that KA-resistant cells lose the WE but continue to conduct glycolysis and surprisingly remain dependent on glucose as a carbon source and also on central carbon metabolism. Consequently, this altered state of glycolysis led to differential metabolic activity and requirements, including emergent activities in and dependences on fatty acid metabolism. These findings reveal that aerobic glycolysis is a process functionally distinct from conventional glucose metabolism and leads to distinct metabolic requirements and biological functions.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.