View source for Warburg effect (oncology)

{{short description|Form of metabolism in tumors}}
{{Use dmy dates|date=March 2023}}
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In oncology, the '''Warburg effect''' ({{IPAc-en|ˈ|v|ɑr|b|ʊər|g}}) is the observation that most cancer use [[aerobic glycolysis]] for energy generation rather than the mechanisms used by non-cancerous cells.<ref name=mis/> This observation was first published by [[Otto Heinrich Warburg]],<ref>{{cite journal |vauthors=Alfarouk KO |date=December 2016 |title=Tumor metabolism, cancer cell transporters, and microenvironmental resistance |journal=Journal of Enzyme Inhibition and Medicinal Chemistry |volume=31 |issue=6 |pages=859–66 |doi=10.3109/14756366.2016.1140753 |pmid=26864256 |doi-access=free}}</ref> who was awarded the 1931 [[Nobel Prize in Physiology or Medicine|Nobel Prize in Physiology]] for his "discovery of the nature and mode of action of the respiratory enzyme".<ref>{{Cite web |title=The Nobel Prize in Physiology or Medicine 1931 |url=https://www.nobelprize.org/nobel_prizes/medicine/laureates/1931/ |access-date=20 April 2007 |publisher=Nobel Foundation}}</ref> The existence of the Warburg effect has fuelled popular misconceptions that cancer can be treated by dietary reductions in sugar and carbohydrate, according to an article in the Lancet.<ref name=mis/>
In [[fermentation]], the last product of glycolysis, pyruvate, is converted into lactate ([[lactic acid fermentation]]) or ethanol ([[alcoholic fermentation]]). 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 [[catabolism|catabolic]] oxidation of such nutrients into [[carbon dioxide]], preserving [[carbon-carbon bond]]s and promoting [[anabolism]].<ref name="Heiden-Cantley">{{cite journal | vauthors = Vander Heiden MG, Cantley LC, Thompson CB | title = Understanding the Warburg effect: the metabolic requirements of cell proliferation | journal = Science | volume = 324 | issue = 5930 | pages = 1029–1033 | date = May 2009 | pmid = 19460998 | pmc = 2849637 | doi = 10.1126/science.1160809 | bibcode = 2009Sci...324.1029V }}</ref>{{Failed verification|reason=The above sentence does not reflect the actual conditions of a balance between electron disposal and use of carbohydrate backbones for biosynthesis purposes, and the cited source does not provide evidence for the statements made here.|date=February 2024}}
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.<ref name="pmid25184270">{{cite journal | vauthors = Batra S, Adekola KU, Rosen ST, Shanmugam M | title = Cancer metabolism as a therapeutic target | journal = Oncology | location = Williston Park, N.Y. | volume = 27 | issue = 5 | pages = 460–467 | date = May 2013 | pmid = 25184270 }}</ref>
== 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 fermentation|aerobic glycolysis]]". The phenomenon was later termed Warburg effect after its discoverer.<ref name=":02">{{cite journal | vauthors = Vander Heiden MG, Cantley LC, Thompson CB | title = Understanding the Warburg effect: the metabolic requirements of cell proliferation | journal = Science | volume = 324 | issue = 5930 | pages = 1029–33 | date = May 2009 | pmid = 19460998 | pmc = 2849637 | doi = 10.1126/science.1160809 | bibcode = 2009Sci...324.1029V }}</ref> Warburg [[Warburg hypothesis|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.<ref name="Liberti_2016" />
== 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.<ref name=":02" /> 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.<ref name="Liberti_2016">{{cite journal | vauthors = Liberti MV, Locasale JW | title = The Warburg Effect: How Does it Benefit Cancer Cells? | journal = Trends in Biochemical Sciences | volume = 41 | issue = 3 | pages = 211–218 | date = March 2016 | pmid = 26778478 | pmc = 4783224 | doi = 10.1016/j.tibs.2015.12.001 | type = Review }}</ref>
Otto Warburg postulated this change in metabolism is the fundamental cause of cancer,<ref name="pmid13298683">{{cite journal | vauthors = Warburg O | title = On the origin of cancer cells | journal = Science | volume = 123 | issue = 3191 | pages = 309–14 | date = February 1956 | pmid = 13298683 | doi = 10.1126/science.123.3191.309 | bibcode = 1956Sci...123..309W }}</ref> a claim now known as the [[Warburg hypothesis]]. Today, [[mutation]]s in [[oncogene]]s and [[tumor suppressor gene]]s 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.<ref>{{cite journal | vauthors = Bertram JS | title = The molecular biology of cancer | journal = Molecular Aspects of Medicine | volume = 21 | issue = 6 | pages = 167–223 | date = December 2000 | pmid = 11173079 | doi = 10.1016/S0098-2997(00)00007-8 | s2cid = 24155688 }}</ref><ref>{{cite journal | vauthors = Grandér D | s2cid = 12467031 | title = How do mutated oncogenes and tumor suppressor genes cause cancer? | journal = Medical Oncology | volume = 15 | issue = 1 | pages = 20–6 | date = April 1998 | pmid = 9643526 | doi = 10.1007/BF02787340 }}</ref>
==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.<ref>{{cite journal | vauthors = López-Lázaro M | title = The Warburg effect: why and how do cancer cells activate glycolysis in the presence of oxygen? | journal = Anti-Cancer Agents in Medicinal Chemistry | volume = 8 | issue = 3 | pages = 305–12 | date = April 2008 | pmid = 18393789 | doi = 10.2174/187152008783961932 }}</ref> 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 bond]]s 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.<ref name="Heiden-Cantley" /> Such trade-offs can be theoretically associated with [[Giffen good|Giffen behavior]] in economics.<ref>{{cite journal | vauthors = Yamagishi JF, Hatakeyama TS | title = Microeconomics of Metabolism: The Warburg Effect as Giffen Behaviour | journal = Bulletin of Mathematical Biology | volume = 83 | issue = 12 | date = November 2021 | page = 120 | doi = 10.1007/s11538-021-00952-x | pmid = 34718881 | pmc = 8558188 | doi-access = free }}</ref>
Evidence attributes some of the high anaerobic glycolytic rates to an overexpressed form of mitochondrially-bound [[hexokinase]]<ref>{{cite journal | vauthors = Bustamante E, Pedersen PL | title = High aerobic glycolysis of rat hepatoma cells in culture: role of mitochondrial hexokinase | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 74 | issue = 9 | pages = 3735–9 | date = September 1977 | pmid = 198801 | pmc = 431708 | doi = 10.1073/pnas.74.9.3735 | bibcode = 1977PNAS...74.3735B | doi-access = free }}</ref> 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.<ref>{{cite journal | vauthors = Unwin RD, Craven RA, Harnden P, Hanrahan S, Totty N, Knowles M, Eardley I, Selby PJ, Banks RE | title = Proteomic changes in renal cancer and co-ordinate demonstration of both the glycolytic and mitochondrial aspects of the Warburg effect | journal = Proteomics | volume = 3 | issue = 8 | pages = 1620–32 | date = August 2003 | pmid = 12923786 | doi = 10.1002/pmic.200300464 | s2cid = 8885599 }}</ref> 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.<ref>{{cite journal | vauthors = Gogvadze V, Zhivotovsky B, Orrenius S | title = The Warburg effect and mitochondrial stability in cancer cells | journal = Molecular Aspects of Medicine | volume = 31 | issue = 1 | pages = 60–74 | date = February 2010 | pmid = 19995572 | doi = 10.1016/j.mam.2009.12.004 }}</ref>
=== 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.<ref name = "Niepmann_2024" /> 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.<ref name = "Niepmann_2024">{{cite journal | vauthors = Niepmann M | title = Importance of Michaelis Constants for Cancer Cell Redox Balance and Lactate Secretion-Revisiting the Warburg Effect | journal = Cancers | volume = 16 | issue = 13 | pages = 2290 | date = June 2024 | pmid = 39001354 | pmc = 11240417 | doi = 10.3390/cancers16132290 | doi-access = free }}</ref>
==Molecular targets==
{{asof|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.<ref name="Vander Heiden2013">{{cite journal | vauthors = Vander Heiden MG | title = Exploiting tumor metabolism: challenges for clinical translation | journal = The Journal of Clinical Investigation | volume = 123 | issue = 9 | pages = 3648–51 | date = September 2013 | pmid = 23999437 | pmc = 3754281 | doi = 10.1172/JCI72391 }}</ref> Many substances have been developed which inhibit glycolysis and so have potential as anticancer agents,<ref name="pmid16892078">{{cite journal | vauthors = Pelicano H, Martin DS, Xu RH, Huang P | title = Glycolysis inhibition for anticancer treatment | journal = Oncogene | volume = 25 | issue = 34 | pages = 4633–46 | date = August 2006 | pmid = 16892078 | doi = 10.1038/sj.onc.1209597 | doi-access =  | s2cid = 22155169 }}</ref> 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.<ref>{{ClinicalTrialsGov|NCT00633087|A Phase I/II Trial of 2-Deoxyglucose (2DG) for the Treatment of Advanced Cancer and Hormone Refractory Prostate Cancer (2-Deoxyglucose)}}</ref> {{As of|2017|post=,}} there is no evidence yet to support the use of DCA for cancer treatment.<ref>{{Cite web|url=https://www.cancer.org/treatment/treatments-and-side-effects/complementary-and-alternative-medicine.html|title=Complementary and Alternative Medicine {{!}} American Cancer Society|website=www.cancer.org|access-date=18 October 2017}}</ref>
[[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.<ref>{{cite thesis | vauthors = Colen CB |year= 2005 |title= Gene therapy and radiation of malignant glioma by targeting glioma specific lactate transporter |type= PhD |publisher= Wayne State University |url= http://elibrary.wayne.edu/record=b3043899~S47}}</ref><ref name="pmid17277695">{{cite journal | vauthors = Colen CB, Seraji-Bozorgzad N, Marples B, Galloway MP, Sloan AE, Mathupala SP | title = Metabolic remodeling of malignant gliomas for enhanced sensitization during radiotherapy: an in vitro study | journal = Neurosurgery | volume = 59 | issue = 6 | pages = 1313–23; discussion 1323–4 | date = December 2006 | pmid = 17277695 | pmc = 3385862 | doi = 10.1227/01.NEU.0000249218.65332.BF }}</ref><ref name="pmid21750656">{{cite journal | vauthors = Colen CB, Shen Y, Ghoddoussi F, Yu P, Francis TB, Koch BJ, Monterey MD, Galloway MP, Sloan AE, Mathupala SP | title = Metabolic targeting of lactate efflux by malignant glioma inhibits invasiveness and induces necrosis: an in vivo study | journal = Neoplasia | volume = 13 | issue = 7 | pages = 620–32 | date = July 2011 | pmid = 21750656 | pmc = 3132848 | doi = 10.1593/neo.11134 }}</ref><ref name="pmid17354062">{{cite journal | vauthors = Mathupala SP, Colen CB, Parajuli P, Sloan AE | title = Lactate and malignant tumors: a therapeutic target at the end stage of glycolysis | journal = Journal of Bioenergetics and Biomembranes | volume = 39 | issue = 1 | pages = 73–7 | date = February 2007 | pmid = 17354062 | pmc = 3385854 | doi = 10.1007/s10863-006-9062-x }}</ref> Higher affinity MCT inhibitors have been developed and are currently undergoing clinical trials by Astra-Zeneca.<ref>{{ClinicalTrialsGov|NCT01791595|A Phase I Trial of AZD3965 in Patients With Advanced Cancer}}</ref>
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.<ref name="pmid17222789">{{cite journal | vauthors = Bonnet S, Archer SL, Allalunis-Turner J, Haromy A, Beaulieu C, Thompson R, Lee CT, Lopaschuk GD, Puttagunta L, Bonnet S, Harry G, Hashimoto K, Porter CJ, Andrade MA, Thebaud B, Michelakis ED | title = A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth | journal = Cancer Cell | volume = 11 | issue = 1 | pages = 37–51 | date = January 2007 | pmid = 17222789 | doi = 10.1016/j.ccr.2006.10.020 | doi-access = free }}</ref><ref name="pmid17426345">{{cite journal | vauthors = Pan JG, Mak TW | title = Metabolic targeting as an anticancer strategy: dawn of a new era? | journal = Science's STKE | volume = 2007 | issue = 381 | pages = pe14 | date = April 2007 | pmid = 17426345 | doi = 10.1126/stke.3812007pe14 | s2cid = 37022600 }}</ref>
Pyruvate dehydrogenase catalyses the rate-limiting step in the aerobic oxidation of glucose and pyruvate and links glycolysis to the [[Citric acid cycle|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]].<ref>{{cite journal | vauthors = Tran Q, Lee H, Park J, Kim SH, Park J | title = Targeting Cancer Metabolism - Revisiting the Warburg Effects | journal = Toxicological Research | volume = 32 | issue = 3 | pages = 177–93 | date = July 2016 | pmid = 27437085 | pmc = 4946416 | doi = 10.5487/TR.2016.32.3.177 }}</ref> 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.<ref>{{cite journal | vauthors = Michelakis ED, Webster L, Mackey JR | title = Dichloroacetate (DCA) as a potential metabolic-targeting therapy for cancer | journal = British Journal of Cancer | volume = 99 | issue = 7 | pages = 989–94 | date = October 2008 | pmid = 18766181 | pmc = 2567082 | doi = 10.1038/sj.bjc.6604554 }}</ref>
[[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]].<ref name="pmid18337823">{{cite journal | vauthors = Christofk HR, Vander Heiden MG, Harris MH, Ramanathan A, Gerszten RE, Wei R, Fleming MD, Schreiber SL, Cantley LC | s2cid = 16111842 | title = The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth | journal = Nature | volume = 452 | issue = 7184 | pages = 230–3 | date = March 2008 | pmid = 18337823 | doi = 10.1038/nature06734 | bibcode = 2008Natur.452..230C }}</ref><ref>{{cite journal | vauthors = Pedersen PL | s2cid = 43490722 | title = Warburg, me and Hexokinase 2: Multiple discoveries of key molecular events underlying one of cancers' most common phenotypes, the "Warburg Effect", i.e., elevated glycolysis in the presence of oxygen | journal = Journal of Bioenergetics and Biomembranes | volume = 39 | issue = 3 | pages = 211–22 | date = June 2007 | pmid = 17879147 | doi = 10.1007/s10863-007-9094-x }}</ref>
== Alternative models ==
=== Reverse Warburg effect ===
A model called the "reverse Warburg effect" describes cells releasing energy by glycolysis, but which are not tumor cells, but [[stromal cell|stromal]] [[fibroblast]]s.<ref>{{cite journal | vauthors = Lee M, Yoon JH | title = Metabolic interplay between glycolysis and mitochondrial oxidation: The reverse Warburg effect and its therapeutic implication | journal = World Journal of Biological Chemistry | volume = 6 | issue = 3 | pages = 148–61 | date = August 2015 | pmid = 26322173 | pmc = 4549759 | doi = 10.4331/wjbc.v6.i3.148 | type = Review | doi-access = free }}</ref> 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 aerobic glycolysis.<ref>{{cite journal | vauthors = Pavlides S, Whitaker-Menezes D, Castello-Cros R, Flomenberg N, Witkiewicz AK, Frank PG, Casimiro MC, Wang C, Fortina P, Addya S, Pestell RG, Martinez-Outschoorn UE, Sotgia F, Lisanti MP | title = The reverse Warburg effect: aerobic glycolysis in cancer associated fibroblasts and the tumor stroma | journal = Cell Cycle | volume = 8 | issue = 23 | pages = 3984–4001 | date = December 2009 | pmid = 19923890 | doi = 10.4161/cc.8.23.10238 | doi-access = free }}</ref>
=== Inverse Warburg effect ===
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.<ref>{{cite journal | vauthors = Luis C, Duarte F, Faria I, Jarak I, Oliveira PF, Alves MG, Soares R, Fernandes R | title = Warburg Effect Inversion: Adiposity shifts central primary metabolism in MCF-7 breast cancer cells | journal = Life Sciences | volume = 223 | pages = 38–46 | date = April 2019 | pmid = 30862570 | doi = 10.1016/j.lfs.2019.03.016 | hdl = 10400.22/14163 | s2cid = 76665891 | hdl-access = free }}</ref>
==Cancer metabolism and epigenetics==
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, [[epigenetics|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.<ref>{{cite journal | vauthors = Gupta V, Gopinath P, Iqbal MA, Mazurek S, Wellen KE, Bamezai RN | title = Interplay between epigenetics & cancer metabolism | journal = Current Pharmaceutical Design | volume = 20 | issue = 11 | pages = 1706–14 | year = 2013 | pmid = 23888952 | doi = 10.2174/13816128113199990536 }}</ref>
== Warburg effect in non-cancer cells ==
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 [[CD28|coreceptor CD28]].<ref name=MedzhitovR>{{cite journal | vauthors = Medzhitov R | s2cid = 13252418 | title = Bringing Warburg to lymphocytes | journal = Nature Reviews. Immunology | volume = 15 | issue = 10 | pages = 598 | date = October 2015 | pmid = 26403193 | doi = 10.1038/nri3918 | doi-access = free }}</ref> This CD3/CD28 signaling parallels [[insulin]] signaling, as both lead to higher expression of [[Glucose transporter|glucose transporter 1]] ([[GLUT1|Glut-1]]) on the cell surface via the activation of [[Akt|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.<ref>{{cite journal|author5-link=Jeffrey Rathmell| vauthors = Frauwirth KA, Riley JL, Harris MH, Parry RV, Rathmell JC, Plas DR, Elstrom RL, June CH, Thompson CB | title = The CD28 signaling pathway regulates glucose metabolism | journal = Immunity | volume = 16 | issue = 6 | pages = 769–77 | date = June 2002 | pmid = 12121659 | doi = 10.1016/S1074-7613(02)00323-0 | doi-access = free }}</ref>
== Society and culture ==
The Warburg effect has served as a locus of popular misconceptions that cancer can be treated by reducing food and carbohydrate intake to supposedly "starve" tumours. In reality, the health of people with cancer is best served by maintaining a [[healthy diet]].<ref name=mis>{{cite journal |vauthors=Grimes DR, O'Riordan E |title=Starving cancer and other dangerous dietary misconceptions |journal=Lancet Oncol |volume=24 |issue=11 |pages=1177–1178 |date=November 2023 |pmid=37922928 |doi=10.1016/S1470-2045(23)00483-7 |url=}}</ref>
==See also==
*[[Oncometabolism]]
* [[Overflow metabolism]]
== References ==
{{Reflist}}
{{DEFAULTSORT:Warburg Effect}}
[[Category:Oncology]]