Pyruvate Kinase M2: A Potential Target for Regulating Inflammation

Abstract

Pyruvate kinase (PK) is the enzyme responsible for catalyzing the last step of glycolysis. Of the four PK isoforms expressed in mammalian cells, PKM2 has generated the most interest due to its impact on changes in cellular metabolism observed in cancer as well as in activated immune cells. As our understanding of dysregulated metabolism in cancer develops, and in light of the growing field of immunometabolism, intense efforts are in place to define the mechanism by which PKM2 regulates the metabolic profile of cancer as well as of immune cells. The enzymatic activity of PKM2 is heavily regulated by endogenous allosteric effectors as well as by intracellular signaling pathways, affecting both the enzymatic activity of PKM2 as a PK and the regulation of the recently described non-canonical nuclear functions of PKM2. We here review the current literature on PKM2 and its regulation, and discuss the potential for this protein as a therapeutic target in inflammatory disorders.

Keywords: HIF-1α; PKM2; cancer; glycolysis and oxidative phosphorylation; immunometabolism; inflammation.

Figure 1

Simplified diagram depicting some of the nuclear and glycolytic functions and regulation of PKM2. PKM2 is the major PK isoform expressed in cancer, proliferating cells, and populations of activated immune cells. The activity of PKM2 can be controlled by stabilizing or destabilizing the formation of PKM2 tetramers. Allosteric activation of PKM2 by, for example, succinylaminoimidazolecarboxamide ribose-5′-phosphate (SAICAR), serine, FBP, or small-molecule activators, such as TEPP 46 and DASA 58, encourages tetramer formation of PKM2, thereby promoting the last rate-limiting step of glycolysis, converting PEP to pyruvate. Pyruvate will enter the TCA cycle of the mitochondria where it is used to generate ATP through oxidative phosphorylation. In the absence of allosteric activators PKM2 primarily takes on a dimeric or monomeric form, which through lacking enzymatic activity will give rise to accumulation of glycolytic intermediates, thereby meeting the requirements for biosynthetic precursors of the activated or proliferating cell. Dimeric PKM2 can translocate to the nucleus where it further promotes aerobic glycolysis through Hif-1α co-activation, aiding expression of proglycolytic genes, such as ldha and glut-1, as well as proinflammatory IL-1β. Furthermore, PKM2 can interact with other transcription factors, such as STAT3, as well as histone H3 and JMJD5, thereby further regulating genes important for proliferation and glycolysis.