Pyruvate Kinase PKM2: Basic and Translational Aspects in Molecular Diagnosis of Human Malignancies

Abstract

The M2 isoform of the glycolytic enzyme pyruvate kinase PKM (PKM2) is at a central focus of current research on cancer metabolism. It functions as a highly adaptive metabolic master regulator, orchestrating a switch between modes of (1) energy generation via highly efficient conversion of phosphoenolpyruvate (PEP) to pyruvate yielding ATP, and (2) 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 the PKM2-expressing cells, particularly in malignant tumors exhibiting severely abnormal metabolic demands. Molecular fingerprints of the PKM2-dependent metabolic adaptation, including PKM2 overexpression, shift of the PKM2 tetramer-dimer equilibrium toward the latter, release of the PKM2 dimer into circulation, and spontaneous tumor-associated immune responses against PKM2, may serve 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 in the context of the fundamental aspects of PKM2 biology and historical and modern notions on the PKM2-driven metabolic adaptation.