PKM2, cancer metabolism, and the road ahead

Abstract

A major metabolic aberration associated with cancer is a change in glucose metabolism. Isoform selection of the glycolytic enzyme pyruvate kinase has been implicated in the metabolic phenotype of cancer cells, and specific pyruvate kinase isoforms have been suggested to support divergent energetic and biosynthetic requirements of cells in tumors and normal tissues. PKM2 isoform expression has been closely linked to embryogenesis, tissue repair, and cancer. In contrast, forced expression of the PKM1 isoform has been associated with reduced tumor cell proliferation. Here, we discuss the role that PKM2 plays in cells and provide a historical perspective for how the study of PKM2 has contributed to understanding cancer metabolism. We also review recent studies that raise important questions with regard to the role of PKM2 in both normal and cancer cell metabolism.

Keywords: PKM2; cancer metabolism; glycolysis; pyruvate kinase.

Figure 1. Overview of cancer metabolism

Schematic illustrating the relationship between some of the metabolic pathways altered in cancer cells. Metabolic enzymes implicated in cancer are depicted in blue boxes.

Figure 2. Pyruvate kinase: 2 genes, 4 isoforms

There are two pyruvate kinase genes, PKLR and PKM. PKLR encodes the PKL and PKR isoforms through tissue‐specific promoters (shown in purple for PKR and orange for PKL). PKM encodes the PKM1 and PKM2 isoforms through alternative splicing of the mutually exclusive exons 9 and 10 (shown in blue and red, respectively). Each of the pyruvate kinase isoforms shows a distinct pattern of tissue expression.

Figure 3. A timeline of key events in the study of PKM2

hPK, human pyruvate kinase.

Figure 4. Overview of cellular signaling events that modulate PKM2 enzymatic activity

Schematic showing endogenous activators and inhibitors of PKM2 activity. PKM2 is only enzymatically active as a tetramer. Thus, allosteric regulation is achieved through stabilization or destabilization of the enzyme tetramer. PKM2 is activated by the upstream glycolytic intermediate FBP. It can also be activated by a number of unique allosteric effectors including serine and SAICAR. PKM2 activity can be inhibited by a number of endogenous inhibitors and cellular signaling events including alanine, ATP, and the thyroid hormone T3. In addition, PKM2 activity is inhibited by phospho‐tyrosine‐mediated release of FBP. Other post‐translational modifications that inhibit PKM2 activity include acetylation and oxidation.