A critical review of the role of M2PYK in the Warburg effect

Abstract

It is becoming generally accepted in recent literature that the Warburg effect in cancer depends on inhibition of M 2 PYK, the pyruvate kinase isozyme most commonly expressed in tumors. We remain skeptical. There continues to be a general lack of solid experimental evidence for the underlying idea that a bottle neck in aerobic glycolysis at the level of M 2 PYK results in an expanded pool of glycolytic intermediates (which are thought to serve as building blocks necessary for proliferation and growth of cancer cells). If a bottle neck at M 2 PYK exists, then the remarkable increase in lactate production by cancer cells is a paradox, particularly since a high percentage of the carbons of lactate originate from glucose. The finding that pyruvate kinase activity is invariantly increased rather than decreased in cancer undermines the logic of the M 2 PYK bottle neck, but is consistent with high lactate production. The "inactive" state of M 2 PYK in cancer is often described as a dimer (with reduced substrate affinity) that has dissociated from an active tetramer of M 2 PYK. Although M 2 PYK clearly dissociates easier than other isozymes of pyruvate kinase, it is not clear that dissociation of the tetramer occurs in vivo when ligands are present that promote tetramer formation. Furthermore, it is also not clear whether the dissociated dimer retains any activity at all. A number of non-canonical functions for M 2 PYK have been proposed, all of which can be challenged by the finding that not all cancer cell types are dependent on M 2 PYK expression. Additional in-depth studies of the Warburg effect and specifically of the possible regulatory role of M 2 PYK in the Warburg effect are needed.

Pyruvate kinase controls signal strength in the insulin secretory pathway

“…Time-resolved stable isotope measurements identify that OxPhos and anaplerosis are anti-phase with each other and suggests that mitochondria choose not to oxidize and synthesize simultaneously. In light of this, the phenomenon of PK-associated Warburg metabolism, while often considered for its ATP-generating capacity, may be even more important for its ADP lowering capacity (Harris and Fenton, 2019). Just as in β-cells, ADP deprivation may shift mitochondrial activity from OxPhos into the biosynthesis of essential nutrients needed to support cell division, or the generation of reactive oxygen species used for signaling.…”

Cancer‐associated mutations in human pyruvate kinase M2 impair enzyme activity

“…Mammalian pyruvate kinase isoforms function as homotetramers to catalyze the final step of glycolysis, which is the transfer of phosphate from phosphoenolpyruvate (PEP) to ADP to produce pyruvate and ATP. There are four mammalian pyruvate kinase isoforms, and the activity of each isoform is regulated in a manner that suits its physiological role . The muscle (PKM1) isoform is found in nonproliferating and highly catabolic tissues such as the heart, brain, and skeletal muscle, where it functions as a highly active, constitutive tetramer with few regulatory inputs .…”

“…While some pyruvate kinase enzyme activity is retained in these mutants, the effects of these mutations on enzyme kinetics have not been well characterized. To understand how these mutations affect PKM2 function in proliferating cells, kinetic characterization is necessary, particularly in light of controversy surrounding the proposed functions of PKM2 .…”

An overview of structure, function, and regulation of pyruvate kinases

“…Additional mechanisms for regulation of PyK‐M2, such as the nitrosylation of specific Cys residues have also been proposed . However, PyK‐M2 is also present in normal cells, and currently there is no evidence of a metabolic shift to this isozyme during tumorigenesis . Therefore, additional studies are needed to establish how regulation of PyK‐M2 might support the altered glucose metabolism in cancer cells and the metabolic re‐routing of glucose from cellular respiration to its increased utilization in the biosynthesis of macromolecules in proliferating cells …”