In oncology, the Warburg effect () is the observation that most cancers use aerobic glycolysis and lactic acid fermentation for energy generation rather than the mechanisms used by non-cancerous cells. This observation was first published by Otto Heinrich Warburg, who was awarded the 1931 Nobel Prize in Physiology for his "discovery of the nature and mode of action of the respiratory enzyme". In fermentation, the last product of glycolysis, pyruvate, is converted into lactate or ethanol. While fermentation produces adenosine triphosphate (ATP) only in low yield compared to the citric acid cycle and oxidative phosphorylation of aerobic respiration, it allows proliferating cells to convert nutrients such as glucose and glutamine more efficiently into biomass by avoiding unnecessary catabolic oxidation of such nutrients into carbon dioxide, preserving carbon-carbon bonds and promoting anabolism. Diagnostically the increased glucose consumption by cancer cells resulting from the Warburg effect is the basis for tumor detection in a PET scan, in which an injected radioactive glucose analog is detected at higher concentrations in malignant cancers than in other tissues. The existence of the Warburg effect has fuelled popular misconceptions that cancer can be treated by dietary reductions in sugar and carbohydrate.
Warburg's research Around the 1920s, Otto Heinrich Warburg and his group concluded that deprivation of glucose and oxygen in tumor cells leads to a lack of energy, resulting in cell death. Biochemist Herbert Grace Crabtree further extended Warburg's research by discovering environmental or genetic influences. Crabtree observed that yeast, Saccharomyces cerevisiae, prefer fermentation leading to ethanol production over aerobic respiration, in aerobic conditions and in the presence of a high concentration of glucose - the Crabtree effect. Warburg observed a similar phenomenon in tumors - cancer cells tend to use fermentation for obtaining energy even in aerobic conditions - coining the term "aerobic glycolysis". The phenomenon was later termed Warburg effect after its discoverer. Warburg hypothesized that dysfunctional mitochondria may be the cause of the higher rate of glycolysis seen in tumor cells, as well as a predominant cause of cancer development.
Basis Normal cells primarily release energy through glycolysis followed by mitochondrial citric acid cycle and oxidative phosphorylation. However, most cancer cells predominantly release energy through a high rate of glycolysis followed by lactic acid fermentation even in the presence of abundant oxygen. Anaerobic glycolysis is less efficient than oxidative phosphorylation for producing adenosine triphosphate and leads to the increased generation of additional metabolites that may particularly benefit proliferating cells. The Warburg effect has been much studied, but its precise nature remains unclear, which hampers the beginning of any work that would explore its therapeutic potential. Otto Warburg postulated this change in metabolism is the fundamental cause of cancer, a claim now known as the Warburg hypothesis. Today, mutations in oncogenes and tumor suppressor genes are thought to be responsible for malignant transformation, and the Warburg effect is considered to be a result of these mutations rather than a cause.
Driving forces Older hypotheses such as the Warburg hypothesis suggest the Warburg effect may simply be a consequence of damage to the mitochondria in cancer. It may also be an adaptation to low-oxygen environments within tumors, or a result of cancer genes shutting down the mitochondria, which are involved in the cell's apoptosis program that kills cancer cells.
Fermentation favors cell proliferation Since glycolysis provides most of the building blocks required for cell proliferation, both cancer cells and normal proliferating cells have been proposed to need to activate glycolysis, despite the presence of oxygen, to proliferate. Inefficient ATP production is only a problem when nutrients are scarce, but anaerobic glycolysis is favored when nutrients are abundant. Anaerobic glycolysis favors anabolism and avoids oxidizing precious carbon-carbon bonds into carbon dioxide. In contrast, oxidative phosphorylation is associated with starvation metabolism and favored when nutrients are scarce and cells must maximize free energy extraction to survive. Such trade-offs can be theoretically associated with Giffen behavior in economics. Evidence attributes some of the high anaerobic glycolytic rates to an overexpressed form of mitochondrially-bound hexokinase responsible for driving the high glycolytic activity. In kidney cancer, this effect could be due to the presence of mutations in the von Hippel–Lindau tumor suppressor gene upregulating glycolytic enzymes, including the M2 splice isoform of pyruvate kinase. TP53 mutation hits energy metabolism and increases glycolysis in breast cancer. The Warburg effect is associated with glucose uptake and use, as this ties into how mitochondrial activity is regulated. The concern lies less in mitochondrial damage and more in the change in activity. On the other hand, tumor cells exhibit increased rates of glycolysis which can be explained with mitochondrial damage.
Disposal of surplus electrons In cancer cells, major changes in gene expression increase glucose uptake to support their rapid growth. Unlike normal cells, which produce lactate only when oxygen is low, cancer cells convert much of the glucose to lactate even in the presence of adequate oxygen. This is known as the “Warburg Effect.” The exact reasons for this are not fully understood, but it has been hypothesized that cancer cells create lactate to manage excess cytosolic electrons that the mitochondria cannot process. The enzymes involved in pyruvate metabolism prioritize: 1) efficient ATP production via mitochondrial oxidative phosphorylation, 2) disposal of excess cytosolic electrons as lactate, and 3) biosynthesis for growth. Essentially, lactate secretion acts as disposal mechanism for surplus electrons, maintaining cellular balance.
… excerpt ends here. Continue reading the full article.
