Fig. 3

The control of aerobic glycolysis by ERK and JNK signaling pathways in proliferating cells. Glycolysis (red-dotted shape) starts when glucose enters the cells through GLUTs and is converted into glucose-6-phosphate by the first glycolytic enzyme hexokinase (HK). The final product of glycolysis is pyruvate. Its production is tightly regulated by the glycolytic enzyme PKM2, whose activation, conformational state, and cellular localization is tightly regulated by posttranslational modifications, which includes phosphorylation, cysteine oxidation, and acetylation. Pyruvate could be further oxidized in the mitochondrion through its conversion to acetyl-CoA for subsequent oxidation in the tricarboxylic acid (TCA) cycle. The shunting of pyruvate into the mitochondrion is regulated by the activity of pyruvate dehydrogenase (PDH), which in turn is negatively regulated by pyruvate dehydrogenase kinases (PDKs) under hypoxia. In proliferating cells, a largest amount of pyruvate is converted to lactate contributing to the Warburg effect. The formation of lactate, catalyzed by lactate dehydrogenase (LDH), is necessary for the rapid regeneration of NAD⁺ from NADH, which is then reused to maintain active the glycolytic flux. Aerobic glycolysis of cells in multicellular organisms is regulated by both extracellular and intracellular signaling pathways. Engagement of growth factors to their receptors signals activation of PI3K/AKT pathway and the phosphorylation cascade of RAS/BRAF/MEK/ERK (green-dotted shape). The BRAF/MEK/ERK signaling cascade can be also activated by oncogenic mutations and culminates with activation and translocation of ERK to the nucleus, which regulates the expression and activity of transcription factors that directly control the expression of glycolytic enzymes in cancer cells. This network of transcription factors, including hypoxia-inducible factor-1α (HIF-1α) and c-Myc, drives the Warburg effect downstream of oncogenic BRAF(V600E) mutation in melanomas. Binding and activation of MEK by BRAF is further enhanced after accumulation in the cytoplasm of acetoacetate, a byproduct of ketogenesis—a biochemical process by which cells produce ketone bodies by the breakdown of fatty acids and ketogenic amino acids such as glutamine (gray-dotted shape). RAS-mediated oncogenesis and cellular stress also contribute to the activation of JNK cascade (blue-dotted shape). Once activated, upstream MAP3K kinases (e.g., TAK1 and MLK3) phosphorylate and activate MKK4 and MKK7, which in turn phosphorylate and stimulate the activity of distinct JNK isoforms. Upon activation, each JNK protein delivers different cellular activities. While JNK1 negatively regulates aerobic glycolysis via direct phosphorylation of PKM2 and PDH, JNK2 positively controls aerobic glycolysis via upregulation of PARP14, a direct inhibitor of JNK1-mediated phosphorylation of PKM2 in cancer cells. Notably, JNK1 activation depends also on the formation and accumulation of mitochondrial and cellular ROS