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 synthesis of DNA and lipids required for cell proliferation and NADPH 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.

JMJD5 regulates PKM2 nuclear translocation and reprograms HIF-1α–mediated glucose metabolism

“…Significantly, knockdown of JMJD5 correlates with the reduced glucose uptake, lactate secretion, and decreased expression of genes in the glycolytic flux either under normoxia or hypoxia, implicating a role in linking PKM2 in glucose metabolism (14). Several lines of evidence strongly suggest that JMJD5 regulates PKM2's tumorigenic capability: (i) JMJD5 binds to PKM2, hinders PKM2 tetramerization, and blocks pyruvate kinase activity; (ii) JMJD5 positively affects the nuclear translocation of PKM2; (iii) Both proteins are hypoxia-inducible in breast cancer cells and JMJD5 promotes PKM2-HIF-1α-mediated transactivation activity; and (iv) JMJD5 and PKM2 are corecruited to the HRE sites at the LDHA and PKM2 loci, promoting the HIF-1-mediated activity (6).…”

“…PKM2 is located at a "gate" position in the glycolytic flux to respond to various stimuli crucial for the Warburg effect (6). Its unique integrative capability relies on a specific alternative- Fold enrichments normalized to IgG are presented (mean ± SD; n = 9 from three independent experiments).…”

“…This generally involves an increased uptake of glucose, use of intracellular glucose to pyruvate via glycolysis, and the conversion into lactate in the presence of sufficient oxygen. Along this metabolic flux, PKM1 or its spliced variant, PKM2, which dephosphorylates phosphoenolpyruvate (PEP) into pyruvate, the last step of glycolysis, is an important signal integrator whose activities determine the cytosolic level of pyruvate, thereby affecting subsequent metabolic flow to lactate, tricarboxylic acid cycle or biosynthetic pathway (6). Enzymatically, PKM2, an embryonic isoform found abundantly in tumor cells, is less active than PKM1, which allows the accumulation of glycolytic intermediates and diversion into biosynthetic pathways, demanded by rapid-proliferating cells.…”

Nuclear PKM2 regulates the Warburg effect

“…2 Increased PKM2 expression has also been detected in cancer-associated fibroblasts. 3 In response to epidermal growth factor (EGF) receptor (EGFR) activation, PKM2 is upregulated by NFκB-mediated PKM gene transcription.…”

Applications of Nutrigenomics in Animal Sectors: A Review

“…So glucose has significant role in cancer cell. Changes in the expression of glucose responsive gene such as pyruvate kinase type M2 and phosphofructokinase1might be an alternative treatment of cancer (Yi et al, 2012;Luo and Semenza, 2012). Fruit and vegetables are primary sources of vitamins and mineral that have potential role in cancer prevention.…”