In plant physiology, the Warburg's effect is the decrease in the rate of photosynthesis by high oxygen concentrations. Oxygen is a competitive inhibitor of the carbon dioxide fixation by RuBisCO which initiates photosynthesis. Furthermore, oxygen stimulates photorespiration which reduces photosynthetic output. These two mechanisms working together are responsible for the Warburg effect.
In oncology, the Warburg effect is the observation that most cancer cells predominantly produce energy by a high rate of glycolysis followed by lactic acid fermentation in the cytosol, rather than by a comparatively low rate of glycolysis followed by oxidation of pyruvate in mitochondria as in most normal cells. The latter process is aerobic (uses oxygen). Malignant, rapidly growing tumor cells typically have glycolytic rates up to 200 times higher than those of their normal tissues of origin; this occurs even if oxygen is plentiful.
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.
The Warburg effect may simply be a consequence of damage to the mitochondria in cancer, or 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. It may also be an effect associated with cell proliferation. Since glycolysis provides most of the building blocks required for cell proliferation, cancer cells (and normal proliferating cells) have been proposed to need to activate glycolysis, despite the presence of oxygen, to proliferate. Evidence attributes some of the high aerobic 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.
In March 2008, Lewis C. Cantley and colleagues announced that the tumor M2-PK, a form of the pyruvate kinase enzyme, gives rise to 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; but PKM2 was identified in all of the cancer cells they had tested. This enzyme form is not usually found in healthy tissue, though it is apparently necessary when cells need to multiply quickly, e.g. in healing wounds or hematopoiesis.
Many substances have been developed which inhibit glycolysis, and such inhibitors are currently the subject of intense research 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). Clinical trials are ongoing for 2-DG and 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 cancers.
Blood glucose levels
High glucose levels have been shown to accelerate cancer cell proliferation in vitro, while glucose deprivation has led to apoptosis. These findings have initiated further study of the effects of carbohydrate restriction on tumor growth. Clinical evidence shows that lower blood glucose levels in late-stage cancer patients have been correlated with better outcomes.
A model called the "reverse Warburg effect" describes cells producing energy by glycolysis, but were not tumor cells, but stromal fibroblasts. Although the Warburg effect would exist in certain cancer types potentially, it highlighted the need for a closer look at tumor metabolism.
Metabolic reprogramming is also observed in neurodegenerative diseases, Alzheimer's and Parkinson's. This metabolic alteration is described by the up-regulation of oxidative phosphorylation - called the inverse Warburg Effect. This is in contrast to healthy neurons, where synaptic activity promotes a neuronal Warburg Effect that is thought to underlie neuronal growth and structural plasticity, and – by reducing the rate of oxidative phosphorylation and the generation of reactive oxygen species – may contribute to synaptic activity-dependent neuroprotection.
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.
- Turner JS, Brittain EG (February 1962). "Oxygen as a factor in photosynthesis" (PDF). Biological Reviews of the Cambridge Philosophical Society. 37: 130–70. PMID 13923215. doi:10.1111/j.1469-185X.1962.tb01607.x.
- Zelitch I (1971). "Chapter 8, Section E: Inhibition by O2 (The Warburg Effect)". Photosynthesis, Photorespiration, and Plant Productivity. New York: Academic Press. pp. 253–255. ISBN 0124316085.
- Schopfer P, Mohr H (1995). "The leaf as a photosynthetic system". Plant physiology. Berlin: Springer. pp. 236–237. ISBN 3-540-58016-6.
- Alfarouk KO, Verduzco D, Rauch C, Muddathir AK, Adil HH, Elhassan GO, Ibrahim ME, David Polo Orozco J, Cardone RA, Reshkin SJ, Harguindey S (2014). "Glycolysis, tumor metabolism, cancer growth and dissemination. A new pH-based etiopathogenic perspective and therapeutic approach to an old cancer question". Oncoscience. 1 (12): 777–802. PMC . PMID 25621294. doi:10.18632/oncoscience.109.
- Alfarouk KO (February 2016). "Tumor metabolism, cancer cell transporters, and microenvironmental resistance". Journal of Enzyme Inhibition and Medicinal Chemistry: 1–8. PMID 26864256. doi:10.3109/14756366.2016.1140753.
- Alfarouk KO, Muddathir AK, Shayoub ME (20 January 2011). "Tumor acidity as evolutionary spite". Cancers. 3 (1): 408–14. PMC . PMID 24310355. doi:10.3390/cancers3010408.
- Gatenby RA, Gillies RJ (November 2004). "Why do cancers have high aerobic glycolysis?". Nature Reviews. Cancer. 4 (11): 891–9. PMID 15516961. doi:10.1038/nrc1478.
- Kim JW, Dang CV (September 2006). "Cancer's molecular sweet tooth and the Warburg effect". Cancer Research. 66 (18): 8927–30. PMID 16982728. doi:10.1158/0008-5472.CAN-06-1501.
- Liberti MV, Locasale JW (2016). "The Warburg Effect: How Does it Benefit Cancer Cells?". Trends Biochem. Sci. (Review). 41 (3): 211–8. PMC . PMID 26778478. doi:10.1016/j.tibs.2015.12.001.
- Warburg O (February 1956). "On the origin of cancer cells". Science. 123 (3191): 309–14. Bibcode:1956Sci...123..309W. PMID 13298683. doi:10.1126/science.123.3191.309.
- Bertram JS (December 2000). "The molecular biology of cancer". Molecular Aspects of Medicine. 21 (6): 167–223. PMID 11173079. doi:10.1016/S0098-2997(00)00007-8.
- Grandér D (April 1998). "How do mutated oncogenes and tumor suppressor genes cause cancer?". Medical Oncology. 15 (1): 20–6. PMID 9643526. doi:10.1007/BF02787340.
- 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. PMID 18393789. doi:10.2174/187152008783961932.
- 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. PMC . PMID 198801. doi:10.1073/pnas.74.9.3735.
- Unwin RD, Craven RA, Harnden P, Hanrahan S, Totty N, Knowles M, Eardley I, Selby PJ, Banks RE (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. PMID 12923786. doi:10.1002/pmic.200300464.
- Harami-Papp, Hajnalka; Pongor, Lőrinc S.; Munkácsy, Gyöngyi; Horváth, Gergő; Nagy, Ádám M.; Ambrus, Attila; Hauser, Péter; Szabó, András; Tretter, László (2016-08-25). "TP53 mutation hits energy metabolism and increases glycolysis in breast cancer". Oncotarget. 7 (41). ISSN 1949-2553. PMC . PMID 27582538. doi:10.18632/oncotarget.11594.
- Christofk HR, Vander Heiden MG, Harris MH, Ramanathan A, Gerszten RE, Wei R, Fleming MD, Schreiber SL, Cantley LC (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. PMID 18337823. doi:10.1038/nature06734.
- 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. PMID 17879147. doi:10.1007/s10863-007-9094-x.
- Pelicano H, Martin DS, Xu RH, Huang P (August 2006). "Glycolysis inhibition for anticancer treatment". Oncogene. 25 (34): 4633–46. PMID 16892078. doi:10.1038/sj.onc.1209597.
- 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
- 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. PMC . PMID 17277695. doi:10.1227/01.NEU.0000249218.65332.BF.
- Colen CB, Shen Y, Ghoddoussi F, Yu P, Francis TB, Koch BJ, Monterey MD, Galloway MP, Sloan AE, Mathupala SP (July 2011). "Metabolic targeting of lactate efflux by malignant glioma inhibits invasiveness and induces necrosis: an in vivo study". Neoplasia. 13 (7): 620–32. PMC . PMID 21750656. doi:10.1593/neo.11134.
- 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. PMC . PMID 17354062. doi:10.1007/s10863-006-9062-x.
- 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, Lee CT, Lopaschuk GD, Puttagunta L, Bonnet S, Harry G, Hashimoto K, Porter CJ, Andrade MA, Thebaud B, Michelakis ED (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. PMID 17222789. doi:10.1016/j.ccr.2006.10.020.
- Pan JG, Mak TW (April 2007). "Metabolic targeting as an anticancer strategy: dawn of a new era?". Science's STKE. 2007 (381): pe14. PMID 17426345. doi:10.1126/stke.3812007pe14.
- Klement RJ, Kämmerer U (2011). "Is there a role for carbohydrate restriction in the treatment and prevention of cancer?". Nutrition & Metabolism. 8: 75. PMC . PMID 22029671. doi:10.1186/1743-7075-8-75.
- Lee M, Yoon JH (2015). "Metabolic interplay between glycolysis and mitochondrial oxidation: The reverse Warburg effect and its therapeutic implication". World J Biol Chem (Review). 6 (3): 148–61. PMC . PMID 26322173. doi:10.4331/wjbc.v6.i3.148.
- 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 (December 2009). "The reverse Warburg effect: aerobic glycolysis in cancer associated fibroblasts and the tumor stroma". Cell Cycle. 8 (23): 3984–4001. PMID 19923890. doi:10.4161/cc.8.23.10238.
- Alfarouk KO, Shayoub ME, Muddathir AK, Elhassan GO, Bashir AH (22 July 2011). "Evolution of Tumor Metabolism might Reflect Carcinogenesis as a Reverse Evolution process (Dismantling of Multicellularity)". Cancers. 3 (4): 3002–17. PMC . PMID 24310356. doi:10.3390/cancers3033002.
- Bas-Orth, Carlos; Tan, Yan-Wei; Lau, David; Bading, Hilmar (2017-03-31). "Synaptic Activity Drives a Genomic Program That Promotes a Neuronal Warburg Effect". The Journal of Biological Chemistry. 292 (13): 5183–5194. ISSN 1083-351X. PMC . PMID 28196867. doi:10.1074/jbc.M116.761106.
- Goyal, Manu S.; Hawrylycz, Michael; Miller, Jeremy A.; Snyder, Abraham Z.; Raichle, Marcus E. (2014-01-07). "Aerobic glycolysis in the human brain is associated with development and neotenous gene expression". Cell Metabolism. 19 (1): 49–57. ISSN 1932-7420. PMC . PMID 24411938. doi:10.1016/j.cmet.2013.11.020.
- Newington, Jordan T.; Pitts, Andrea; Chien, Andrew; Arseneault, Robert; Schubert, David; Cumming, Robert C. (2011-04-26). "Amyloid beta resistance in nerve cell lines is mediated by the Warburg effect". PloS One. 6 (4): e19191. ISSN 1932-6203. PMC . PMID 21541279. doi:10.1371/journal.pone.0019191.
- Newington, Jordan T.; Rappon, Tim; Albers, Shawn; Wong, Daisy Y.; Rylett, R. Jane; Cumming, Robert C. (2012-10-26). "Overexpression of pyruvate dehydrogenase kinase 1 and lactate dehydrogenase A in nerve cells confers resistance to amyloid β and other toxins by decreasing mitochondrial respiration and reactive oxygen species production". The Journal of Biological Chemistry. 287 (44): 37245–37258. ISSN 1083-351X. PMC . PMID 22948140. doi:10.1074/jbc.M112.366195.
- 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. PMID 23888952. doi:10.2174/13816128113199990536.