What is the Warburg Effect

What is the Warburg Effect

Roles nutrients play in the biochemistry of a cell Thus, proliferating cells must acquire more nutrients, convert them into biosynthetic building blocks, and coordinate the reactions necessary to transform them into the macromolecules essential for constructing a new cell. We have yet to fully understand how cells Regulate biochemical pathways to allocate nutrients to provide free energy, mostly in the form of ATP, that allows otherwise unfavorable biochemical reactions, while simultaneously fueling the anabolic processes needed to grow and to produce new cells. By definition, cancer involves the inappropriate proliferation of cells, and the metabolic phenotype of cancer cells must represent a solution that regulates metabolic pathways to achieve a balance between ATP production and biomass production. However, this solution is not unique to cancer, as many phenotypes found in cancer cells also exist in normal proliferating cells and fast-growing unicellular organisms.

Figure 1 Metabolic pathways active in proliferating cells. This schematic represents our current understanding of how glycolysis, oxidative phosphorylation, the pentose phosphate pathway, and glutamine metabolism contribute to biomass precursors. Enzymes that control critical steps and are often overexpressed or mutated in cancer cells are shown in dark blue. Nucleotides that can be incorporated into DNA and RNA are highlighted in light blue, representative lipids are highlighted in green, and nonessential amino acids are highlighted in orange. Some key metabolites that serve as important precursors for biomass production are boxed. Glucose and glutamine, the major carbon sources in most proliferating cells, are shown; however, other metabolites can serve as carbon sources if available. In mitochondria, conversion between glutamate and α-ketoglutarate requires NAD(P)/NAD(P)H only if catalyzed byglutamate dh.

Apoptosis is a genetically controlled mechanism of cell death that is essential for the elimination of unwanted cells during normal development and for the maintenance of tissue homeostasis. One of the major apoptosis signaling pathways involves the p53 tumour suppressor. Tumor protein p53 is a nuclear transcription factor that regulates the expression of a wide variety of genes involved in apoptosis, growth arrest or senescence in response to genotoxic or cellular stress.

Cancers cells strongly s5mulate glycolysis and glutaminolysis for their biosynthesis. Pyruvate derived from glucose is preferen5ally diverted towards the produc5on of lac5c acid (Warburg effect). Citrate censors ATP produc5on and controls strategic enzymes of anabolic and catabolic pathways through feedback reac5ons. Mitochondrial citrate diffuses in the cytosol to restore oxaloacetate and acetyl- CoA. Whereas acetyl- CoA serves de novo lipid synthesis and histone acetyla5on, OAA is derived towards lactate produc5on via pyruvate and / or a vicious cycle reforming mitochondrial citrate. This cycle allows cancer cells to burn their host's lipid and protein reserves in order to sustain their own biosynthesis pathways. In vitro, citrate has demonstrated an5- cancer proper5es when administered in excess, sensi5zing cancer cells to chemotherapy. Understanding its central role is of par5cular relevance for the development of new strategies for counterac5ng cancer cell prolifera5on and overcoming chemoresistance.

Glucose metabolism in cancer cells most onen results in the forma5on of lac5c acid, even in the presence of oxygen. This phenomenon, referred to as aerobic glycolysis or the Warburg effect is increasingl ystudied. It is a reversal of the Pasteur effect (inhibi5on of fermenta5on by O2); modifica5ons of the Pasteur effect in cancer cells are linked, among others, to Hypoxia- induc5ble factor 1 (HIF1). HIF1 s5mulates many target glycoly5c enzyme genes, whereas it blocks the use of pyruvate by mitochondrial pyruvate dehydrogenase (PDH). These mechanisms produce a shin from oxida5ve phosphoryla5on (OXPHOS) to glycolysis for producing ATP. In normal cells, the Pasteur effect is mediated by ATP and citrate. In hypoxic condi5ons, full glucose oxida5on is decreased, resul5ng in a decrease in ATP and citrate produced by mitochondria. In turn, the feedback of these molecules on PFK1, the main regulator enzyme for glycolysis, is break down. Glycolysis is then accelerated, leading to enhanced produc5on of lac5c acid.