More Than Meets the Eye Regarding Cancer Metabolism

Abstract

In spite of the continuous improvement in our knowledge of the nature of cancer, the causes of its formation and the development of new treatment methods, our knowledge is still incomplete. A key issue is the difference in metabolism between normal and cancer cells. The features that distinguish cancer cells from normal cells are the increased proliferation and abnormal differentiation and maturation of these cells, which are due to regulatory changes in the emerging tumour. Normal cells use oxidative phosphorylation (OXPHOS) in the mitochondrion as a major source of energy during division. During OXPHOS, there are 36 ATP molecules produced from one molecule of glucose, in contrast to glycolysis which provides an ATP supply of only two molecules. Although aerobic glucose metabolism is more efficient, metabolism based on intensive glycolysis provides intermediate metabolites necessary for the synthesis of nucleic acids, proteins and lipids, which are in constant high demand due to the intense cell division in cancer. This is the main reason why the cancer cell does not "give up" on glycolysis despite the high demand for energy in the form of ATP. One of the evolving trends in the development of anti-cancer therapies is to exploit differences in the metabolism of normal cells and cancer cells. Currently constructed therapies, based on cell metabolism, focus on the attempt to reprogram the metabolic pathways of the cell in such a manner that it becomes possible to stop unrestrained proliferation.

Keywords: Warburg effect; cancer metabolism; glutamine; glycolysis; lactate; tumour heterogeneity.

Figure 1

Comparison of cancer and normal cell metabolism. The glucose molecule is transferred to the cells by glucose transporters (GLUT). In normal cells, glucose is metabolised to two pyruvate molecules. Pyruvate in the presence of oxygen passes to the mitochondrion, where it is oxidized to acetyl-CoA and then incorporated into the Krebs cycle. Nevertheless, the pentose phosphate cycle can be an alternative glucose metabolism. The main function of this process is the production of NADPH. In cancer cells, the expression of glucose transporters is increased, and anaerobic respiration is encouraged, even with optimal oxygen availability. A significantly increased activity of some glycolytic enzymes and phosphofructokinase 2 and an increased pentose phosphate cycle activity are observed. The increase in activity is marked in red. Created with BioRender.com.

Figure 2

The impact of hypoxia and normoxia on glucose and glutamine metabolism in cancer cells. The increase in activity is shown in red and the decrease in blue. Adapted from “Cancer Metabolism”, by BioRender.com (2021). Retrieved from https://app.biorender.com/biorender-templates.

Figure 3

Graphical illustration of issues related to the heterogeneity of cancer metabolic phenotypes. Created with BioRender.com.