Interconnection between Metabolism and Cell Cycle in Cancer.

ABSTRACT

Cell cycle progression and division is regulated by checkpoint controls and sequential activation of cyclin-dependent kinases (CDKs). Understanding of how these events occur in synchrony with metabolic changes could have important therapeutic implications. For biosynthesis, cancer cells enhance glucose and glutamine consumption. Inactivation of pyruvate kinase M2 (PKM2) promotes transcription in G1 phase. Glutamine metabolism supports DNA replication in S phase and lipid synthesis in G2 phase. A boost in glycolysis and oxidative metabolism can temporarily furnish more ATP when necessary (G1/S transition, segregation of chromosomes). Recent studies have shown that a few metabolic enzymes [PKM2, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase (PFKFB3), GAPDH] also periodically translocate to the nucleus and oversee cell cycle regulators or oncogene expression (c-Myc). Targeting these metabolic enzymes could increase the response to CDK inhibitors (CKIs).