The Pkm2 Pyruvate Kinase Isoform: The Basic and Translational Aspects in the Context of the Molecular Diagnosis of Human Malignancies

The M2 isoform of the glycolytic enzyme pyruvate kinase PKM (PKM2) represents a central focus of contemporary research in cancer metabolism. It functions as a highly adaptive metabolic master regulator, orchestrating a switch between modes of 1) energy generation via the highly efficient conversion of phosphoenolpyruvate (PEP) to pyruvate yielding ATP, and 2) the accumulation of glycolytic intermediates, which are funneled into various biosynthetic pathways (i.e., biosynthesis of amino acids, nucleotides, and fatty acids). Characterized by exceptional functional and regulatory plasticity, PKM2 represents an ideal tool for metabolic adaptation in PKM2-expressing cells, particularly in malignant tumors exhibiting severely abnormal metabolic demands. The molecular fingerprints of PKM2-dependent metabolic adaptation, including PKM2 overexpression, shift of the PKM2 tetramer-dimer equilibrium toward the latter, release of the PKM2 dimer into the circulation, and spontaneous tumor-associated immune responses against PKM2, may act as biomarkers in a wide spectrum of human malignancies. This review provides a comprehensive analysis of the potential of PKM2-dependent metabolic fingerprinting in the diagnosis of human malignancies, with a broader contextualization of this data within the fundamentals of PKM2 biology and historical and contemporary perspectives on PKM2-driven metabolic adaptation.