Publications

Normal cells grow and divide only when instructed to by signaling pathways stimulated by exogenous growth factors. A nearly ubiquitous feature of cancer cells is their capacity to grow independent of such signals, in an uncontrolled, cell-intrinsic manner. This property arises due to the frequent oncogenic activation of core growth factor signaling pathway components, including receptor tyrosine kinases, PI3K-AKT, RAS-RAF, mTORC1, and MYC, leading to the aberrant propagation of pro-growth signals independent of exogenous growth factors. The growth of both normal and cancer cells requires the acquisition of nutrients and their anabolic conversion to the primary macromolecules underlying biomass production (protein, nucleic acids, and lipids). The core growth factor signaling pathways exert tight regulation of these metabolic processes and the oncogenic activation of these pathways drive the key metabolic properties of cancer cells and tumors. Here, we review the molecular mechanisms through which these growth signaling pathways control and coordinate cancer metabolism.

The tricarboxylic acid cycle, nutrient oxidation, histone acetylation and synthesis of lipids, glycans and haem all require the cofactor coenzyme A (CoA). Although the sources and regulation of the acyl groups carried by CoA for these processes are heavily studied, a key underlying question is less often considered: how is production of CoA itself controlled? Here, we discuss the many cellular roles of CoA and the regulatory mechanisms that govern its biosynthesis from cysteine, ATP and the essential nutrient pantothenate (vitamin B₅), or from salvaged precursors in mammals. Metabolite feedback and signalling mechanisms involving acetyl-CoA, other acyl-CoAs, acyl-carnitines, MYC, p53, PPARα, PINK1 and insulin- and growth factor-stimulated PI3K-AKT signalling regulate the vitamin B₅ transporter SLC5A6/SMVT and CoA biosynthesis enzymes PANK1, PANK2, PANK3, PANK4 and COASY. We also discuss methods for measuring CoA-related metabolites, compounds that target CoA biosynthesis and diseases caused by mutations in pathway enzymes including types of cataracts, cardiomyopathy and neurodegeneration (PKAN and COPAN).