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

Publication date: Available online 29 January 2019Source: Biochimica et Biophysica Acta (BBA) - Reviews on CancerAuthor(s): Robert A. Harris, Aron W. FentonAbstractIt is becoming generally accepted in recent literature that the Warburg effect in cancer depends on inhibition of M2PYK, 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 M2PYK 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 M2PYK 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 M2PYK bottle neck, but is consistent with high lactate production. The “inactive” state of M2PYK in cancer is often described as a dimer (with reduced substrate affinity) that has dissociated from an active tetramer of M2PYK. Although M2PYK 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 dissoc...
Source: Biochimica et Biophysica Acta (BBA) Reviews on Cancer - Category: Cancer & Oncology Source Type: research