The role of glycolysis in tumorigenesis: From biological aspects to therapeutic opportunities

Abstract

Glycolytic metabolism generates energy and intermediates for biomass production. Tumor-associated glycolysis is upregulated compared to normal tissues in response to tumor cell-autonomous or non-autonomous stimuli. The consequences of this upregulation are twofold. First, the metabolic effects of glycolysis become predominant over those mediated by oxidative metabolism. Second, overexpressed components of the glycolytic pathway (i.e. enzymes or metabolites) acquire new functions unrelated to their metabolic effects and which are referred to as "moonlighting" functions. These functions include induction of mutations and other tumor-initiating events, effects on cancer stem cells, induction of increased expression and/or activity of oncoproteins, epigenetic and transcriptional modifications, bypassing of senescence and induction of proliferation, promotion of DNA damage repair and prevention of DNA damage, antiapoptotic effects, inhibition of drug influx or increase of drug efflux. Upregulated metabolic functions and acquisition of new, non-metabolic functions lead to biological effects that support tumorigenesis: promotion of tumor initiation, stimulation of tumor cell proliferation and primary tumor growth, induction of epithelial-mesenchymal transition, autophagy and metastasis, immunosuppressive effects, induction of drug resistance and effects on tumor accessory cells. These effects have negative consequences on the prognosis of tumor patients. On these grounds, it does not come to surprise that tumor-associated glycolysis has become a target of interest in antitumor drug discovery. So far, however, clinical results with glycolysis inhibitors have fallen short of expectations. In this review we propose approaches that may allow to bypass some of the difficulties that have been encountered so far with the therapeutic use of glycolysis inhibitors.

Keywords: Anticancer therapies; Cancer stem cells; Glycolysis; Metabolic reprogramming; Tumorigenesis.

Fig. 1

Glycolytic metabolism. The figure shows glycolytic enzymes and metabolites as well as metabolic pathways that branch off from glycolysis. ATP, adenosine triphosphate; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; GPI, glucose 6-phosphate isomerase; GLUT, glucose transporter; HK, hexokinase; LDH, lactate dehydrogenase; MCT, monocarboxylate transporter; NAD+, nicotinamide adenine dinucleotide oxidized; NADH, NAD reduced; PDH, pyruvate dehydrogenase; PFK, phosphofructokinase; PGK, phosphoglycerate kinase; PGM, phosphoglycerate mutase; PK, pyruvate kinase; TCA, tricarboxylic acid; TPI, triosephosphate isomerase.

Fig. 2

Molecular effects of upregulated tumor glycolysis. These effects can be broadly classified into two categories: metabolic consequences and induction of “moonlighting" functions which, in turn, are classified into the indicated subcategories. ATP, adenosine triphosphate; DDR, DNA damage response; OXPHOS, oxidative phosphorylation; ROS, reactive oxygen species.

Fig. 3

Biological effects of upregulated tumor glycolysis. The molecular effects of upregulated tumor glycolysis translate into a series of biological effects that are depicted here and discussed under section 4.2. EMT, epithelial-mesenchymal transition.

Fig. 4

Tumor targeting of inhibitors of glycolytic and oxidative metabolism. A) Administration of inhibitors of glycolytic metabolism may induce metabolic reprogramming towards oxidative metabolism in tumor cells allowing them to bypass the antitumor effects of the inhibitors. B) Administration of inhibitors that block both glycolytic as well as oxidative metabolism may be required in order to achieve efficacious antitumor activity. An approach of this kind however, may be accompanied by unacceptable side effects. In order to avoid these effects, it is proposed to take advantage of tumor targeting approaches, allowing to deliver the drug(s) preferentially to tumor cells while sparing normal cells.