The ERK and JNK pathways in the regulation of metabolic reprogramming

Abstract

Most tumor cells reprogram their glucose metabolism as a result of mutations in oncogenes and tumor suppressors, leading to the constitutive activation of signaling pathways involved in cell growth. This metabolic reprogramming, known as aerobic glycolysis or the Warburg effect, allows tumor cells to sustain their fast proliferation and evade apoptosis. Interfering with oncogenic signaling pathways that regulate the Warburg effect in cancer cells has therefore become an attractive anticancer strategy. However, evidence for the occurrence of the Warburg effect in physiological processes has also been documented. As such, close consideration of which signaling pathways are beneficial targets and the effect of their inhibition on physiological processes are essential. The MAPK/ERK and MAPK/JNK pathways, crucial for normal cellular responses to extracellular stimuli, have recently emerged as key regulators of the Warburg effect during tumorigenesis and normal cellular functions. In this review, we summarize our current understanding of the roles of the ERK and JNK pathways in controlling the Warburg effect in cancer and discuss their implication in controlling this metabolic reprogramming in physiological processes and opportunities for targeting their downstream effectors for therapeutic purposes.

Fig. 1

Schematic diagram of glycolysis. Schematic drawing shows the steps and specific enzymes of the glycolytic pathway that converts glucose in pyruvate through a series of enzymatic reactions catalyzed by hexokinase (HK), phosphoglucose isomerase (PGI), phosphofructokinase (PFK), aldolase (ALDOA), glyceraldehyde 3 phosphate dehydrogenase (GAPDH), phosphoglycerate kinase (PGK), phosphoglycerate mutase (PGM), enolase (ENO), and pyruvate kinase (PK). Lactate dehydrogenase (LDH) converts pyruvate in lactate. Shown are also the biosynthetic pathways that originate from glycolytic intermediates

Fig. 2

Cellular functions associated with aerobic glycolysis: to proliferation and beyond. Aerobic glycolysis has been widely linked to cell proliferation, especially in cancer cells where it serves to generate sufficient energy (by means of ATP) and synthesis of building blocks needed for cell growth and division. Aerobic glycolysis provides also antioxidant capacity to many different cells (i.e., cancer cells, immune cells, neurons, and stem cells) to protect against oxidative stress-induced apoptosis and provide survival advantages. Other than serving as an antiapoptotic pathway, aerobic glycolysis is crucially required for specific cellular functions: (i) biosynthesis of neurotransmitters, (ii) activation and differentiation of specialized cells, (iii) antimicrobial activity, and (iv) naive to primed pluripotency

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

Fig. 4

ERK- and JNK-mediated phosphorylation of PKM2 is at the crossroad between proliferation and apoptosis. PKM2 acts as master regulator of the Warburg effect. Of the many posttranslational modifications, phosphorylation of PKM2 by either ERK or JNK1 dictates distinct outcomes. In quiescent cells, PKM2 is present as a tetrameric protein associated with elevated enzymatic activity. When cells receive a growth stimulus, activation of ERK drives phosphorylation of tetrameric PKM2. Phosphorylated PKM2 is then cis-trans isomerized by PIN1 allowing dissociation of tetrameric PKM2 to monomers. Monomeric PKM2 enters the nucleus where it acts as histone-binding protein allowing gene expression regulation of both glycolytic enzymes and cell cycle regulators (i.e., c-Myc, cyclin D1). Besides, accumulation of reactive oxygen species (ROS) in the cytoplasm promotes activation of JNK1, which can phosphorylate and enhance PKM2 activation, allowing cells to reduce their antioxidant capacity and induce apoptosis. Notably, enhanced expression of PARP14 in cancer cells suppresses JNK1-mediated phosphorylation and activation of PKM2, providing therefore survival advantages to cancer cells. PARP14 by suppressing JNK1 activity contributes to maintain low PKM2 activity and, combined with a robust glycolysis, leads to an accumulation of glycolytic intermediates, including precursors of nucleic acids, lipids, and amino acids. This accumulation provides a metabolic bottleneck allowing glycolytic intermediates to be redirected toward biosynthesis, fueling through the pentose phosphate pathway for DNA synthesis and thereby contributing to the rapid cell proliferation seen in tumors