Balancing glycolytic flux: the role of 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatases in cancer metabolism

Abstract

The increased glucose metabolism in cancer cells is required to fulfill their high energetic and biosynthetic demands. Changes in the metabolic activity of cancer cells are caused by the activation of oncogenes or loss of tumor suppressors. They can also be part of the metabolic adaptations to the conditions imposed by the tumor microenvironment, such as the hypoxia response. Among the metabolic enzymes that are modulated by these factors are the 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatases (PFKFBs), a family of bifunctional enzymes that control the levels of fructose 2,6-bisphosphate (Fru-2,6-P2). This metabolite is important for the dynamic regulation of glycolytic flux by allosterically activating the rate-limiting enzyme of glycolysis phosphofructokinase-1 (PFK-1). Therapeutic strategies designed to alter the levels of this metabolite are likely to interfere with the metabolic balance of cancer cells, and could lead to a reduction in cancer cell proliferation, invasiveness and survival. This article will review our current understanding of the role of PFKFB proteins in the control of cancer metabolism and discuss the emerging interest in these enzymes as potential targets for the development of antineoplastic agents.

Figure 1

PFK-2/FBPase-2 control of glycolysis and gluconeogenic pathways. Overview of glycolysis and gluconeogenesis. Enzymes: phosphofructokinase (PFK-1), fructose 1,6-bisphosphatase (FBPase), 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatases (PFK-2/FBPase-2), pyruvate kinase (PK). Fructose 2,6-bisphosphate is an activator of PFK-1 and inhibitor of FBPase. Fructose 1,6-bisphosphate is an activator of PK. The rest of the enzymes and cofactors have been omitted for simplicity.

Figure 2

Relative activity of 6-phosphofructo-2-kinase (PFK-2)/fructose 1,6-bisphosphatase (FBPase-2). Properties of the PFK-2/FBPase-2 enzymes. Information on chromosomal location and relative enzymatic activity of the different isoforms has been taken from Okar et al. Trends BiochemSci (2001) [7].

Figure 3

Domain organizations and phosphorylation of 6-phosphofructo-2-kinase (PFK-2)/fructose 1,6-bisphosphatase (FBPase-2) isoenzymes. The N-terminal PFK-2 domain is shown in red, the C-terminal FBPase-2 domain is shown in blue and the regulatory domains are shown in green. Phosphorylation sites and the kinases responsible of their phosphorylation are indicated on each main isoforms. The domain structure of human PFK-2/FBPase-2 enzymes is based on Rider et al. Biochem J (2014) [10].

Figure 4

Role of 6-phosphofructo-2-kinase (PFK-2)/fructose 1,6-bisphosphatase (FBPase)-2 in the balance between glycolytic flux and redox regulation. Glucose-6-phosphate fulfills glycolysis, glycogen synthesis and pentose phosphate pathways. The scheme shows how the PFK-2 or the FBPase-2 activity could be crucial in controlling the balance between glycolytic flux and redox regulation by the pentose phosphate pathway for nicotinamide adenine dinucleotide phosphate (NADPH) production. Enzymes: phosphofructokinase (PFK-1), phosphofructokinase 2/fructose 2,6-bisphosphatase (PFK-2/FBPase-2), TIGAR (FBPase-2 activity). Fructose 2,6-bisphosphate is an activator of PFK-1 and inhibitor of FBPase.