A critical review of the role of M 2 PYK in the Warburg effect

It is becoming generally accepted in recent literature that the Warburg effect in cancer depends on inhibition of M 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 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 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 PYK bottle neck, but is consistent with high lactate production. The "inactive" state of M PYK in cancer is often described as a dimer (with reduced substrate affinity) that has dissociated from an active tetramer of M PYK. Although M 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 PYK have been proposed, all of which can be challenged by the finding that not all cancer cell types are dependent on M PYK expression. Additional in-depth studies of the Warburg effect and specifically of the possible regulatory role of M PYK in the Warburg effect are needed.