Emerging roles of PKM2 in cell metabolism and cancer progression

Abstract

Increased conversion of glucose to lactate is a key feature of many cancer cells that promotes rapid growth. Pyruvate kinase M2 (PKM2) expression is increased and facilitates lactate production in cancer cells. Modulation of PKM2 catalytic activity also regulates the synthesis of DNA and lipids that are required for cell proliferation, and of NADPH that is required for redox homeostasis. In addition to its role as a pyruvate kinase, PKM2 also functions as a protein kinase and as a transcriptional coactivator. These biochemical activities are controlled by allosteric regulators and post-translational modifications of PKM2 that include acetylation, oxidation, phosphorylation, prolyl hydroxylation, and sumoylation. Given its pleiotropic effects on cancer biology, PKM2 represents an attractive target for cancer therapy.

Figure 1. PKM2 promotes the Warburg effect and tumor growth

Expression of PKM2 promotes glucose uptake and lactate production and inhibits O₂ consumption in cancer cells, by coactivation of hypoxia-inducible factor 1 (HIF-1)-mediated gene transcription. Expression of the less active PKM2 dimer leads to the accumulation of upstream glycolytic metabolites, which include 3-phosphoglycerate (3-P-glycerate) that stimulates serine synthesis, and phosphoenopyruvate (PEP) and glucose-6-phosphate that stimulate the pentose phosphate pathway (PPP), thereby promoting macromolecule biosynthesis and inhibiting intracellular reactive oxygen species (ROS) generation. PKM2 also translocates into the nucleus to stimulate the activity of transcription factors including HIF-1, HIF-2, β-catenin, STAT3, and Oct-4, thereby increasing the expression of gene products that are required for tumor growth.

Figure 2. Regulation of expression of pyruvate kinase isoforms

(A) PKM1 and PKM2 are produced from PKM2 gene through the alternative RNA splicing of the primary transcript. SRSF3 binds to an exonic splicing enhancer element in the exon 10 region to activate exon 10 inclusion, whereas high levels of heterogenous nuclear ribonucleoproteins (hnRNP) I, hnRNPA1, and hnRNPA2 (shown in green) bind to the intronic sequences flanking exon 9 and inhibit exon 9 inclusion in PKM2 mRNA. Low levels of hnRNPI, hnRNPA1, and hnRNPA2 (shown in grey) bind to intronic sequences flanking exon 10 and inhibit exon 10 inclusion in PKM1 mRNA. (B) PKR and PKL are encoded by PKLR gene and expressed under the control of tissue-specific promoters [64]. The transcription of PKR mRNA is initiated from exon 1 and exon 2 is spliced out of the mature mRNA, whereas the transcription of PKL mRNA is initiated from exon 2 of PKLR.

Figure 3. Feed-forward regulation of PKM2-HIF-1α and PKM2-MYC signaling

HIF-1 activates transcription of PKM2, leading to increased synthesis of PKM2 protein, which in turn promotes HIF-1-dependent gene transcription that mediates angiogenesis and metabolic reprogramming in cancer cells. Similarly, MYC controls PKM2 gene transcription directly and PKM2 mRNA splicing indirectly. PKM2 also stimulates EGF-induced transcription of the β-catenin target gene MYC, which may regulate PKM2-mediated cell proliferation and metabolic reprogramming in cancer cells.