Nonmetabolic functions of pyruvate kinase isoform M2 in controlling cell cycle progression and tumorigenesis

Pyruvate kinase catalyzes the rate-limiting final step of glycolysis, generating adenosine triphosphate (ATP) and pyruvate. The M2 tumor-specific isoform of pyruvate kinase (PKM2) promotes glucose uptake and lactate production in the presence of oxygen, known as aerobic glycolysis or the Warburg effect. As recently reported in Nature, PKM2, besides its metabolic function, has a nonmetabolic function in the direct control of cell cycle progression by activating β-catenin and inducing expression of the β-catenin downstream gene CCND1 (encoding for cyclin D1). This nonmetabolic function of PKM2 is essential for epidermal growth factor receptor (EGFR) activation-induced tumorigenesis.

Regulation of tumor cell migration by protein tyrosine phosphatase (PTP)-proline-, glutamate-, serine-,and threonine-rich sequence(PEST)

Protein tyrosine phosphatase (PTP)-proline-,glutamate-,serine-,and threonine-rich sequence (PEST) is ubiquitously expressed and is a critical regulator of cell adhesion and migration.PTP-PEST activity can be regulated transcriptionally via gene deletion or mutation in several types of human cancers or via post-translational modifications,including phosphorylation,oxidation,and caspase-dependent cleavage.PTP-PEST interacts with and dephosphorylates cytoskeletal and focal adhesion-associated proteins.Dephos-phorylation of PTP-PEST substrates regulates their enzymatic activities and/or their interaction with other proteins and plays an essential role in the tumor cell migration process.

Metabolic features of cancer cells

Cancer cells uniquely reprogram their cellular activities to support their rapid proliferation and migration and to coun-teract metabolic and genotoxic stress during cancer progression.In this reprograming,cancer cells’metabolism and other cellular activities are integrated and mutually regulated,and cancer cells modulate metabolic enzymes spatially and temporally so that these enzymes not only have altered metabolic activities but also have modulated subcellular localization and gain non-canonical functions.This review and several others in this issue of Cancer Communications discuss these enzymes’newly acquired functions and the non-canonical functions of some metabolites as features of cancer cell metabolism,which play critical roles in various cellular activities,including gene expression,anabolism,catabolism,redox homeostasis,and DNA repair.

Nonmetabolic functions of metabolic enzymes in cancer development

Metabolism is a fundamental biological process composed of a series of reactions catalyzed by metabolic enzymes.Emerging evidence demonstrates that the aberrant signaling in cancer cells induces nonmetabolic functions of meta-bolic enzymes in many instrumental cellular activities,which involve metabolic enzyme-mediated protein post-trans-lational modifications,such as phosphorylation,acetylation,and succinylation.In the most well-researched literatures,metabolic enzymes phosphorylate proteins rather than their metabolites as substrates.Some metabolic enzymes have altered subcellular localization,which allows their metabolic products to directly participate in nonmetabolic activities.This review discusses how these findings have deepened our understanding on enzymes originally classi-fied as metabolic enzymes,by highlighting the nonmetabolic functions of several metabolic enzymes responsible for the development of cancer,and evaluates the potential for targeting these functions in cancer treatment.