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Warburg effect (oncology)

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In oncology, the Warburg effect (/ˈvɑːrbʊərɡ/) is the observation that most cancer cells take up increased amounts of glucose and increase metabolite flux through glycolysis. At the same time, the cells release considerable amounts of lactate, even in the presence of abundant oxygen.[1][2][3] This observation was first published by Otto Heinrich Warburg,[1][2][4] who was awarded the 1931 Nobel Prize in Physiology for his "discovery of the nature and mode of action of the respiratory enzyme".[5]

In this condition, cancer cells take up glucose at an increased rate, while only a part of the carbohydrate backbones is metabolized in the tricarboxylic acid (TCA) cycle (or citric acid cycle). At the same time, the cancer cells secrete considerable amounts of lactate.[6][7][8] Also normal cells can show this metabolic condition, but only under oxygen deprivation (then named anaerobic glycolysis). The reason for that is that the electrons from the reaction of the cytosolic glyceraldehyde-3-phosphate dehydrogenase (GAPDH, also named glycerinaldehyde-3-phosphate dehydrogenase) are transferred to NAD+, reducing it to NADH. Under complete oxygen deprivation conditions, the electrons of this cytosolic NADH cannot be discharged in the mitochondrial electron transport chain (ETC), thereby used for oxidative phosphorylation (OXPHOS) and finally be transferred to oxygen, but they must be disposed in some other way. For this purpose, the electrons from the cytosolic NADH are transferred to the end product of the aerobic glycolysis, pyruvate, yielding lactate. This lactate is then secreted from the cell to get rid of the excess cytosolic electrons, regenerate cytosolic NAD+ and maintain cytosolic redox balance even under oxygen deprivation (anaerobic glycolysis).

Cancer cells, however, upregulate glucose uptake and glycolytic metabolite flux even in the presence of sufficient oxygen. Nevertheless, they secrete large amounts of lactate. This is why Otto Warburg named this condition aerobic glycolysis. In many cancer cells, the corresponding enzymes for glycolysis as well as membrane transporters are upregulated.[6][7][8] The reason for this metabolic reprogramming is that the cancer cells increase glucose uptake and metabolite flux through glycolysis and pentose phosphate pathway (PPP) for providing more metabolites for growth. At the same time, flux through TCA cycle and ETC/OXPHOS is reduced (but not stopped). This allows – on the one hand - ongoing efficient ATP regeneration by OXPHOS but – on the other hand - accumulation of upstream metabolites for growth. Also the electron carrier shuttle systems in the inner mitochondrial membrane (malate-aspartate shuttle, glycerol-3-phosphate shuttle) can be substrate saturated in fast growing cancer cells.[9]

However, the gene expression changes involved in this reprogramming can be assumed to be not very fine tuned but rather coarse. This may result in temporal misbalance between the increased flux of carbohydrate backbones through glycolysis and the reduced capacity of ETC/OXPHOS to transfer the electrons from cytosolic NADH to oxygen. For this reason, the cancer cells must dispose a certain fraction of the electrons from cytosolic NADH to pyruvate and form lactate which is then secreted from the cells. This serves to maintain the cytosolic redox balance.

The activies of TCA cycle and ETC/OXPHOS are not completely stopped in cancer cells since growth of the cells also requires lipids like fatty acids and cholesterol.[6][8] The carbohydrate backbones for these syntheses derive from excess Acetyl-CoA in the mitochondrion. The C2 Acetyl unit is exported from the mitochondrion in the form of citrate in order to feed fatty acid and cholesterol synthesis in the cytosol. This is the reason why TCA cycle and ETC/OXPHOS are not completely stopped in cancer cells, since the electrons from mitochondrial NADH and FADH2 need to be discharged to oxygen to allow carbohydrate flux through and carbon backbone withdrawal from the TCA cycle.

In a similar way, the withdrawal of carbon backbone metabolites from glycolysis for biosynthesis reactions requires disposal of at least a fraction of the electrons from the cytosolic NADH in the ETC and the final transfer of these electrons to oxygen. Otherwise, a quantitave transfer of all electrons from the NADH produced in the GAPDH reaction to pyruvate and the secretion of the resulting lactate would mean that the C6 body of glucose is quantitatively converted to the two C3 bodies of lactate which are then quantitatively secreted from the cell. This would not leave any carbon atoms for biosynthesis purposes. Thus, it is impossible that cells metabolize all imported glucose quantitatively to lactate and at the same time use these carbohydrate backbones for biosyntheses.

The above view is supported by analysis of the Michaelis constants (KM values) of the enzymes metabolizing pyruvate at the pyruvate junction.[8] The mitochondrial pyruvate dehydrogenase (PDH) has a KM value of about 0.2 mM. This means that even at very low pyruvate concentrations PDH converts pyruvate primarily to Acetyl-CoA which feeds the TCA cycle and by that is used for efficient ATP regeneration as well as for lipid biosynthesis. The cytosolic lactate dehydrogenase (LDH) which is responsible for disposing excess cytosolic electrons to pyruvate, forming lactate, has a KM value of 0.1 mM for pyruvate (LDH-B oder LDH-1). The LDH-A (or LDH-5) form which is often upregulated in cancer cells has an even higher KM value of 0.29 mM for pyruvate. In this way, it allows the accumulation of metabolites upstream of pyruvate to support cancer cell growth. This accumulation of upstream metabolites is even further supported by expression of plasma membrane lactate transporters with high KM values (MCT-1 and -4). In contrast, alanine aminotransferase or alanine transaminase (ALT) which converts pyruvate into the amino acid alanine, a building block for cancer cell growth, has a KM value for pyruvate of 2.8 mM. Thereby, ALT uses pyruvate only when all other needs for the use of pyruvate (ATP regeneration and maintenance of cytosolic redox balance) have been covered.[8]

Lactate can be produced by virtually all tissues (including heart muscle), and lactate can be consumed by nearly all tissues (except erythrocytes).[8][10][11][12] Thus, from the above considered KM values it is clear what are the priorities for pyruvate metabolization. First priority is the efficient regeneration of ATP via TCA cycle and ETC/OXPHOS. Second priority is the maintenance of cytosolic redox balance by the LDH reaction, and only third priority is biosynthesis reactions.

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.[13]

Warburg's research

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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.[6][14] 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.[15] Otto Warburg postulated this change in metabolism is the fundamental cause of cancer,[2] a claim now known as the Warburg hypothesis. Today, mutations in oncogenes and tumor suppressor genes are known to be responsible for malignant transformation, and the Warburg effect is considered to be a result of these mutations rather than a cause.[16][17]

Molecular targets

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As of 2013, scientists had been investigating the possibility of therapeutic value presented by the Warburg effect. The increase in nutrient uptake by cancer cells has been considered as a possible treatment target by exploitation of a critical proliferation tool in cancer, but it remains unclear whether this can lead to the development of drugs that have therapeutic benefit.[18] Many substances have been developed which inhibit glycolysis and so have potential as anticancer agents,[19] including SB-204990, 2-deoxy-D-glucose (2DG), 3-bromopyruvate (3-BrPA, bromopyruvic acid, or bromopyruvate), 3-bromo-2-oxopropionate-1-propyl ester (3-BrOP), 5-thioglucose and dichloroacetic acid (DCA).

A clinical trial for 2-DG [2008] showed slow accrual and was terminated.[20] As of 2017, there is no evidence yet to support the use of DCA for cancer treatment.[21]

Alpha-cyano-4-hydroxycinnamic acid (ACCA;CHC), a small-molecule inhibitor of monocarboxylate transporters (MCTs; which prevent lactic acid build up in tumors) has been successfully used as a metabolic target in brain tumor pre-clinical research.[22][23][24][25] Higher affinity MCT inhibitors have been developed and are currently undergoing clinical trials by Astra-Zeneca.[26]

Dichloroacetic acid (DCA), a small-molecule inhibitor of mitochondrial pyruvate dehydrogenase kinase, "downregulates" glycolysis in vitro and in vivo. Researchers at the University of Alberta theorized in 2007 that DCA might have therapeutic benefits against many types of cancer.[27][28]

Pyruvate dehydrogenase catalyses the rate-limiting step in the aerobic oxidation of glucose and pyruvate and links glycolysis to the tricarboxylic acid cycle (TCA). DCA acts a structural analog of pyruvate and activates the pyruvate dehydrogenase complex (PDC) to inhibit pyruvate dehydrogenase kinases, to keep the complex in its un-phosphorylated form. DCA reduces expression of the kinases, preventing the inactivation of the PDC, and allowing the conversion of pyruvate to acetyl-CoA rather than lactate through anaerobic respiration, thereby permitting cellular respiration to continue. Through this mechanism of action, DCA works to counteract the increased production of lactate exhibited by tumor cells by enabling the TCA cycle to metabolize it by oxidative phosphorylation.[29] DCA has not been evaluated as a sole cancer treatment yet, as research on the clinical activity of the drug is still in progress, but it has been shown to be effective when used with other cancer treatments. The neurotoxicity and pharmacokinetics of the drug still need to be monitored but if its evaluations are satisfactory it could be very useful as it is an inexpensive small molecule.[30]

Lewis C. Cantley and colleagues found that tumor M2-PK, a form of the pyruvate kinase enzyme, promotes the Warburg effect. Tumor M2-PK is produced in all rapidly dividing cells and is responsible for enabling cancer cells to consume glucose at an accelerated rate; on forcing the cells to switch to pyruvate kinase's alternative form by inhibiting the production of tumor M2-PK, their growth was curbed. The researchers acknowledged the fact that the exact chemistry of glucose metabolism was likely to vary across different forms of cancer; however, PKM2 was identified in all of the cancer cells they had tested. This enzyme form is not usually found in quiescent tissue, though it is apparently necessary when cells need to multiply quickly, e.g., in healing wounds or hematopoiesis.[31][32]

Alternative models

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Reverse Warburg effect

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A model called the "reverse Warburg effect" describes cells releasing energy by glycolysis, but which are not tumor cells, but stromal fibroblasts.[33] In this scenario, the stroma become corrupted by cancer cells and turn into factories for the synthesis of energy rich nutrients. The cells then take these energy rich nutrients and use them for TCA cycle which is used for oxidative phosphorylation. This results in an energy rich environment that allows for replication of the cancer cells. This still supports Warburg's original observation that tumors show a tendency to create energy through anaerobic glycolysis.[34]

Inverse Warburg effect

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Another model has been described in tumor cells in an obesity model called Warburg effect inversion. Whereas in the reverse model, the stroma of the microenvironment produces energy-rich nutrients, in a context of obesity these nutrients already exist in the bloodstream and in the extracellular fluid (ECF). In this way, highly energetic nutrients enter directly into TCA and later into oxidative phosphorylation, while lactate and glycogenic amino acids take the opposite path to that proposed by Warburg, which is the production of glucose through the consumption of lactate.[35]

Cancer metabolism and epigenetics

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Nutrient use is dramatically altered when cells receive signals to proliferate. Characteristic metabolic changes enable cells to meet the large biosynthetic demands associated with cell growth and division. Changes in rate-limiting glycolytic enzymes redirect metabolism to support growth and proliferation. Metabolic reprogramming in cancer is largely due to the oncogenic activation of signal transduction pathways and transcription factors. Although less well understood, epigenetic mechanisms also contribute to the regulation of metabolic gene expression in cancer. Reciprocally, accumulating evidence suggests that metabolic alterations may affect the epigenome. Understanding the relationship between metabolism and epigenetics in cancer cells may open new avenues for anti-cancer strategies.[36]

Warburg effect in non-cancer cells

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A rapid increase in metabolism is needed during the activation of T lymphocytes, which reside in peripheral blood containing stable concentrations of glucose. As glucose is plentiful, T-cells are able to switch to fast use of glucose using the coreceptor CD28.[37] This CD3/CD28 signaling parallels insulin signaling, as both lead to higher expression of glucose transporter 1 (Glut-1) on the cell surface via the activation of Akt kinase. CD28 signal transduction not only leads to higher glucose uptake but also to an increased rate of glycolysis. Most of the glucose taken up by activated T lymphocytes is metabolised to lactate and dumped out of the cells.[38]

See also

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References

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