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.
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 because they are involved in the cell's apoptosis program which would otherwise kill cancerous 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.
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-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.
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, Brettain EG (February 1962). "Oxygen as a factor in photosynthesis" (PDF). Biol Rev Camb Philos Soc 37: 130–70. doi:10.1111/j.1469-185X.1962.tb01607.x. PMID 13923215.
- 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: 777–802. doi:10.18632/oncoscience.109. PMC 4303887. PMID 25621294.
- Alfarouk, Khalid O.; Muddathir, Abdel Khalig; Shayoub, Mohammed E. A. (20 January 2011). "Tumor Acidity as Evolutionary Spite". Cancers 3 (4): 408–414. doi:10.3390/cancers3010408.
- Gatenby RA; Gillies RJ (2004). "Why do cancers have high aerobic glycolysis?". Nature Reviews Cancer 4 (11): 891–9. doi:10.1038/nrc1478. PMID 15516961.
- Kim JW, Dang CV (2006). "Cancer's molecular sweet tooth and the Warburg effect". Cancer Res. 66 (18): 8927–8930. doi:10.1158/0008-5472.CAN-06-1501. PMID 16982728.
- Warburg O (1956). "On the origin of cancer cells". Science 123 (3191): 309–314. Bibcode:1956Sci...123..309W. doi:10.1126/science.123.3191.309. PMID 13298683.
- Bertram JS (2000). "The molecular biology of cancer". Mol. Aspects Med. 21 (6): 167–223. doi:10.1016/S0098-2997(00)00007-8. PMID 11173079.
- Grandér D (1998). "How do mutated oncogenes and tumor suppressor genes cause cancer?". Med. Oncol. 15 (1): 20–26. doi:10.1007/BF02787340. PMID 9643526.
- Lopez-Lazaro M (2008). "The Warburg effect: why and how do cancer cells activate glycolysis in the presence of oxygen?". Anticancer Agents Med. Chem. 8 (3): 305–312. 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". Proc. Natl. Acad. Sci. U.S.A. 74 (9): 3735–3739. Bibcode:1977PNAS...74.3735B. doi:10.1073/pnas.74.9.3735. PMC 431708. PMID 198801.
- Unwin, Richard D.; Craven, Rachel A.; Harnden, Patricia; Hanrahan, Sarah; Totty, Nick; Knowles, Margaret; Eardley, Ian; Selby, Peter J.; Banks, Rosamonde E. (1 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): 1620–1632. doi:10.1002/pmic.200300464.
- Christofk HR, Vander Heiden MG, Harris MH, Ramanathan A, Gerszten RE, Wei R, Fleming MD, Schreiber SL, Cantley LC (2008). "The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth". Nature 452 (7184): 230–233. Bibcode:2008Natur.452..230C. doi:10.1038/nature06734. PMID 18337823.
- Pedersen PL (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". J. Bioenerg. Biomembr. 39 (3): 211–222. doi:10.1007/s10863-007-9094-x. PMID 17879147.
- Pelicano H, Martin DS, Xu RH, Huang P (2006). "Glycolysis inhibition for anticancer treatment". Oncogene 25 (34): 4633–4646. doi:10.1038/sj.onc.1209597. PMID 16892078.
- See ClinicalTrials.gov.
- Colen, CB, PhD Thesis (2005) http://elibrary.wayne.edu/record=b3043899~S47
- Colen CB, Seraji-Bozorgzad N, Marples B, Galloway MP, Sloan AE, Mathupala SP (2006). "Metabolic remodeling of malignant gliomas for enhanced sensitization during radiotherapy: an in vitro study". Neurosurgery 59 (6): 1313–1323. doi:10.1227/01.NEU.0000249218.65332.BF. PMID 17277695.
- Colen CB, Shen Y, Ghoddoussi F, Yu P, Francis TB, Koch BJ, Monterey MD, Galloway MP, Sloan AE, Mathupala SP (2011). "Metabolic targeting of lactate efflux by malignant glioma inhibits invasiveness and induces necrosis: an in vivo study". Neoplasia 13 (7): 620–632. PMC 3132848. PMID 21750656.
- Mathupala SP, Colen CB, Parajuli P, Sloan AE (2007). "Lactate and malignant tumors: a therapeutic target at the end stage of glycolysis (Review)". J Bioenerg Biomembr. 39 (1): 73–77. doi:10.1007/s10863-006-9062-x. PMID 17354062.
- 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 (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 (2007). "Metabolic targeting as an anticancer strategy: dawn of a new era?". Sci. STKE 2007 (381): pe14–pe14. doi:10.1126/stke.3812007pe14. PMID 17426345.
- Klement Rainer J.; Kammerer Ulrike (2011). "Is there a role for carbohydrate restriction in the treatment and prevention of cancer?". Nutrition & Metabolism 8: 75. doi:10.1186/1743-7075-8-75.
- 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. (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. Cite uses deprecated parameter
- Alfarouk, Khalid O.; Shayoub, Mohammed E.A.; Muddathir, Abdel Khalig; Elhassan, Gamal O.; Bashir, Adil H.H. (22 July 2011). "Evolution of Tumor Metabolism might Reflect Carcinogenesis as a Reverse Evolution process (Dismantling of Multicellularity)". Cancers 3 (4): 3002–3017. doi:10.3390/cancers3033002.
- Gupta, V; Gopinath, P; Iqbal, MA; Mazurek, S; Wellen, KE; Bamezai, RN (2013). "Interplay Between Epigenetics & Cancer Metabolism". Curr Pharm Des. 20 (11): 1706–14. doi:10.2174/13816128113199990536. PMID 23888952.