Warburg effect (oncology)
In oncology, the Warburg effect (//) is a form of modified cellular metabolism found in cancer cells, which tend to favor a specialised fermentation over the aerobic respiration pathway that most other cells of the body prefer. 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 (lactic acid fermentation) or ethanol (alcoholic fermentation). While fermentation does not produce adenosine triphosphate (ATP) in high 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.
Around the 1920s, Otto Heinrich Warburg and his group concluded that deprivation of glucose and oxygen in tumor cells leads to 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, prefers fermentation leading to ethanol production over aerobic respiration, in aerobic conditions and in the presence of a high concentration of glucose - 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 higher rate of glycolysis seen in tumor cells, as well as a predominant cause of cancer development.
Normal cells primarily produce energy through glycolysis followed by mitochondrial citric acid cycle and oxidative phosphorylation. However, most cancer cells predominantly produce their 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 in terms of adenosine triphosphate production, but 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.
Older hypotheses such as the Warburg hypothesis suggests 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 aerobic glycolysis is favored when nutrients are abundant. Aerobic 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.
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 utilization, 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.
As of 2013[update], 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 which have therapeutic benefit. Many substances have been developed which inhibit glycolysis and so have potential as anticancer agents, 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).
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. Higher affinity MCT inhibitors have been developed and are currently undergoing clinical trials by Astra-Zeneca.
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.
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, 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. 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.
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.
Reverse Warburg effect
A model called the "reverse Warburg effect" describes cells producing energy by glycolysis, but which are not tumor cells, but stromal fibroblasts. 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.
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.
Cancer metabolism and epigenetics
Nutrient utilization 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 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 suggest that metabolic alterations may affect the epigenome. Understanding the relation between metabolism and epigenetics in cancer cells may open new avenues for anti-cancer strategies.
Warburg effect in non-cancer cells
Rapid increase in metabolism is needed during 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 utilization of glucose using the coreceptor CD28. 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 glucose taken by activated T lymphocytes is metabolised to lactate and dumped out of the cells. Since activated T lymphocytes display a higher uptake of glucose and prefer glycolysis from oxidative phosphorylation in aerobic conditions, this would suggest that Warburg metabolism is a physiological phenomenon that is not unique to cancer cells.
- Vander Heiden MG, Cantley LC, Thompson CB (2009). "Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation". Science. 324 (5930): 1029–1033. doi:10.1126/science.1160809. PMC 2849637. PMID 19460998.
- Alfarouk KO (December 2016). "Tumor metabolism, cancer cell transporters, and microenvironmental resistance". Journal of Enzyme Inhibition and Medicinal Chemistry. 31 (6): 859–66. doi:10.3109/14756366.2016.1140753. PMID 26864256.
- "The Nobel Prize in Physiology or Medicine 1931". NobelPrize.org. Retrieved April 20, 2007.
- Heiden, Matthew G. Vander; Cantley, Lewis C.; Thompson, Craig B. (2009-05-22). "Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation". Science. 324 (5930): 1029–1033. Bibcode:2009Sci...324.1029V. doi:10.1126/science.1160809. ISSN 0036-8075. PMC 2849637. PMID 19460998.
- Vander Heiden MG, Cantley LC, Thompson CB (May 2009). "Understanding the Warburg effect: the metabolic requirements of cell proliferation". Science. 324 (5930): 1029–33. Bibcode:2009Sci...324.1029V. doi:10.1126/science.1160809. PMC 2849637. PMID 19460998.
- Liberti MV, Locasale JW (March 2016). "The Warburg Effect: How Does it Benefit Cancer Cells?". Trends in Biochemical Sciences (Review). 41 (3): 211–218. doi:10.1016/j.tibs.2015.12.001. PMC 4783224. PMID 26778478.
- Batra, Surabhi, Kehinde U. A. Adekola, Steven T. Rosen, and Mala Shanmugam. “Cancer Metabolism as a Therapeutic Target.” Oncology (Williston Park, N.Y.) 27, no. 5 (May 2013): 460–67.
- Warburg O (February 1956). "On the origin of cancer cells". Science. 123 (3191): 309–14. Bibcode:1956Sci...123..309W. doi:10.1126/science.123.3191.309. PMID 13298683.
- Bertram JS (December 2000). "The molecular biology of cancer". Molecular Aspects of Medicine. 21 (6): 167–223. doi:10.1016/S0098-2997(00)00007-8. PMID 11173079.
- Grandér D (April 1998). "How do mutated oncogenes and tumor suppressor genes cause cancer?". Medical Oncology. 15 (1): 20–6. doi:10.1007/BF02787340. PMID 9643526. S2CID 12467031.
- López-Lázaro M (April 2008). "The warburg effect: why and how do cancer cells activate glycolysis in the presence of oxygen?". Anti-Cancer Agents in Medicinal Chemistry. 8 (3): 305–12. doi:10.2174/187152008783961932. PMID 18393789.
- Bustamante E, Pedersen PL (September 1977). "High aerobic glycolysis of rat hepatoma cells in culture: role of mitochondrial hexokinase". Proceedings of the National Academy of Sciences of the United States of America. 74 (9): 3735–9. Bibcode:1977PNAS...74.3735B. doi:10.1073/pnas.74.9.3735. PMC 431708. PMID 198801.
- Unwin RD, Craven RA, Harnden P, Hanrahan S, Totty N, Knowles M, et al. (August 2003). "Proteomic changes in renal cancer and co-ordinate demonstration of both the glycolytic and mitochondrial aspects of the Warburg effect". Proteomics. 3 (8): 1620–32. doi:10.1002/pmic.200300464. PMID 12923786.
- Gogvadze V, Zhivotovsky B, Orrenius S (February 2010). "The Warburg effect and mitochondrial stability in cancer cells". Molecular Aspects of Medicine. 31 (1): 60–74. doi:10.1016/j.mam.2009.12.004. PMID 19995572.
- Vander Heiden MG (September 2013). "Exploiting tumor metabolism: challenges for clinical translation". The Journal of Clinical Investigation. 123 (9): 3648–51. doi:10.1172/JCI72391. PMC 3754281. PMID 23999437.
- Pelicano H, Martin DS, Xu RH, Huang P (August 2006). "Glycolysis inhibition for anticancer treatment". Oncogene. 25 (34): 4633–46. doi:10.1038/sj.onc.1209597. PMID 16892078.
- Clinical trial number NCT00633087 for "A Phase I/II Trial of 2-Deoxyglucose (2DG) for the Treatment of Advanced Cancer and Hormone Refractory Prostate Cancer (2-Deoxyglucose)" at ClinicalTrials.gov
- "Complementary and Alternative Medicine | American Cancer Society". www.cancer.org. Retrieved 2017-10-18.
- Colen CB (2005). Gene therapy and radiation of malignant glioma by targeting glioma specific lactate transporter (Ph.D.). Wayne State University.
- Colen CB, Seraji-Bozorgzad N, Marples B, Galloway MP, Sloan AE, Mathupala SP (December 2006). "Metabolic remodeling of malignant gliomas for enhanced sensitization during radiotherapy: an in vitro study". Neurosurgery. 59 (6): 1313–23, discussion 1323–4. doi:10.1227/01.NEU.0000249218.65332.BF. PMC 3385862. PMID 17277695.
- Colen CB, Shen Y, Ghoddoussi F, Yu P, Francis TB, Koch BJ, et al. (July 2011). "Metabolic targeting of lactate efflux by malignant glioma inhibits invasiveness and induces necrosis: an in vivo study". Neoplasia. 13 (7): 620–32. doi:10.1593/neo.11134. PMC 3132848. PMID 21750656.
- Mathupala SP, Colen CB, Parajuli P, Sloan AE (February 2007). "Lactate and malignant tumors: a therapeutic target at the end stage of glycolysis". Journal of Bioenergetics and Biomembranes. 39 (1): 73–7. doi:10.1007/s10863-006-9062-x. PMC 3385854. PMID 17354062.
- Clinical trial number NCT01791595 for "A Phase I Trial of AZD3965 in Patients With Advanced Cancer" at ClinicalTrials.gov
- Bonnet S, Archer SL, Allalunis-Turner J, Haromy A, Beaulieu C, Thompson R, et al. (January 2007). "A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth". Cancer Cell. 11 (1): 37–51. doi:10.1016/j.ccr.2006.10.020. PMID 17222789.
- Pan JG, Mak TW (April 2007). "Metabolic targeting as an anticancer strategy: dawn of a new era?". Science's STKE. 2007 (381): pe14. doi:10.1126/stke.3812007pe14. PMID 17426345.
- Tran Q, Lee H, Park J, Kim SH, Park J (July 2016). "Targeting Cancer Metabolism - Revisiting the Warburg Effects". Toxicological Research. 32 (3): 177–93. doi:10.5487/TR.2016.32.3.177. PMC 4946416. PMID 27437085.
- Michelakis ED, Webster L, Mackey JR (October 2008). "Dichloroacetate (DCA) as a potential metabolic-targeting therapy for cancer". British Journal of Cancer. 99 (7): 989–94. doi:10.1038/sj.bjc.6604554. PMC 2567082. PMID 18766181.
- Christofk HR, Vander Heiden MG, Harris MH, Ramanathan A, Gerszten RE, Wei R, et al. (March 2008). "The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth". Nature. 452 (7184): 230–3. Bibcode:2008Natur.452..230C. doi:10.1038/nature06734. PMID 18337823. S2CID 16111842.
- Pedersen PL (June 2007). "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 of Bioenergetics and Biomembranes. 39 (3): 211–22. doi:10.1007/s10863-007-9094-x. PMID 17879147. S2CID 43490722.
- Lee M, Yoon JH (August 2015). "Metabolic interplay between glycolysis and mitochondrial oxidation: The reverse Warburg effect and its therapeutic implication". World Journal of Biological Chemistry (Review). 6 (3): 148–61. doi:10.4331/wjbc.v6.i3.148. PMC 4549759. PMID 26322173.
- Pavlides S, Whitaker-Menezes D, Castello-Cros R, Flomenberg N, Witkiewicz AK, Frank PG, et al. (December 2009). "The reverse Warburg effect: aerobic glycolysis in cancer associated fibroblasts and the tumor stroma". Cell Cycle. 8 (23): 3984–4001. doi:10.4161/cc.8.23.10238. PMID 19923890.
- Luis, Carla; Duarte, Fernanda; Faria, Isabel; Jarak, Ivana; Oliveira, Pedro F.; Alves, Marco G.; Soares, Raquel; Fernandes, Rúben (2019). "Warburg Effect Inversion: Adiposity shifts central primary metabolism in MCF-7 breast cancer cells". Life Sciences. 223: 38–46. doi:10.1016/j.lfs.2019.03.016. PMID 30862570. S2CID 76665891.
- Gupta V, Gopinath P, Iqbal MA, Mazurek S, Wellen KE, Bamezai RN (2013). "Interplay between epigenetics & cancer metabolism". Current Pharmaceutical Design. 20 (11): 1706–14. doi:10.2174/13816128113199990536. PMID 23888952.
- Medzhitov R (October 2015). "Bringing Warburg to lymphocytes". Nature Reviews. Immunology. 15 (10): 598. doi:10.1038/nri3918. PMID 26403193. S2CID 13252418.
- Frauwirth KA, Riley JL, Harris MH, Parry RV, Rathmell JC, Plas DR, et al. (June 2002). "The CD28 signaling pathway regulates glucose metabolism". Immunity. 16 (6): 769–77. doi:10.1016/S1074-7613(02)00323-0. PMID 12121659.