Metabolic pathway alterations that support cell proliferation

Abstract

Proliferating cells adapt metabolism to support the conversion of available nutrients into biomass. How cell metabolism is regulated to balance the production of ATP, metabolite building blocks, and reducing equivalents remains uncertain. Proliferative metabolism often involves an increased rate of glycolysis. A key regulated step in glycolysis is catalyzed by pyruvate kinase to convert phosphoenolpyruvate (PEP) to pyruvate. Surprisingly, there is strong selection for expression of the less active M2 isoform of pyruvate kinase (PKM2) in tumors and other proliferative tissues. Cell growth signals further decrease PKM2 activity, and cells with less active PKM2 use another pathway with separate regulatory properties to convert PEP to pyruvate. One consequence of using this alternative pathway is an accumulation of 3-phosphoglycerate (3PG) that leads to the diversion of 3PG into the serine biosynthesis pathway. In fact, in some cancers a substantial portion of the total glucose flux is directed toward serine synthesis, and genetic evidence suggests that glucose flux into this pathway can promote cell transformation. Environmental conditions can also influence the pathways that cells use to generate biomass with the source of carbon for lipid synthesis changing based on oxygen availability. Together, these findings argue that distinct metabolic phenotypes exist among proliferating cells, and both genetic and environmental factors influence how metabolism is regulated to support cell growth.