Tumor glycolysis as a target for cancer therapy: progress and prospects

Abstract

Altered energy metabolism is a biochemical fingerprint of cancer cells that represents one of the "hallmarks of cancer". This metabolic phenotype is characterized by preferential dependence on glycolysis (the process of conversion of glucose into pyruvate followed by lactate production) for energy production in an oxygen-independent manner. Although glycolysis is less efficient than oxidative phosphorylation in the net yield of adenosine triphosphate (ATP), cancer cells adapt to this mathematical disadvantage by increased glucose up-take, which in turn facilitates a higher rate of glycolysis. Apart from providing cellular energy, the metabolic intermediates of glycolysis also play a pivotal role in macromolecular biosynthesis, thus conferring selective advantage to cancer cells under diminished nutrient supply. Accumulating data also indicate that intracellular ATP is a critical determinant of chemoresistance. Under hypoxic conditions where glycolysis remains the predominant energy producing pathway sensitizing cancer cells would require intracellular depletion of ATP by inhibition of glycolysis. Together, the oncogenic regulation of glycolysis and multifaceted roles of glycolytic components underscore the biological significance of tumor glycolysis. Thus targeting glycolysis remains attractive for therapeutic intervention. Several preclinical investigations have indeed demonstrated the effectiveness of this therapeutic approach thereby supporting its scientific rationale. Recent reviews have provided a wealth of information on the biochemical targets of glycolysis and their inhibitors. The objective of this review is to present the most recent research on the cancer-specific role of glycolytic enzymes including their non-glycolytic functions in order to explore the potential for therapeutic opportunities. Further, we discuss the translational potential of emerging drug candidates in light of technical advances in treatment modalities such as image-guided targeted delivery of cancer therapeutics.

Figure 1

Non-glycolytic functions of glycolytic enzymes and metabolic intermediates. In the innermost circle, thick arrows represent enzymes and thin arrows indicate intermediate metabolites. The short arrows pointing towards the outer circle represent the non-glycolytic functions of corresponding enzymes/metabolites.

Figure 2

Schematic showing the distribution of glycolytic enzymes in various subcellular compartments. HKII is a cytoplasmic enzyme however its localization to mitochondrial membrane has been established. As for binding with tubulin or actin filaments existing data are strong enough to include only GAPDH and for other glycolytic enzymes it remains to be known. The nuclear translocation has been well documented for the enzymes GAPDH, LDH, PFKFB3 and PK-M2.

Figure 3

Diagram showing the two phases of glycolysis and the molecular targets currently exploited for potential therapeutic drug strategies. Energy molecules such as ATP and NADH are highlighted in yellow, black arrows indicate consumption while red arrows indicate the energy release. The enzymes involved in respective reactions are abbreviated and encircled, where as the block symbol shows the targets exploited for drug development in preclinical investigations.