Warburg effect
Encyclopedia
The phrase "Warburg effect" is used for two unrelated observations in biochemistry
, one in plant physiology
and the other in oncology
, both due to Nobel laureate Otto Heinrich Warburg
.
fixation
, and subsequently of photosynthesis
, by high oxygen
concentrations.
The oxygenase
activity of RuBisCO
, which initiates the process of photorespiration
, largely accounts for this effect.
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 like most normal cells. The latter process is aerobic
(uses oxygen). Malignant rapidly-growing tumor
cells typically have glycolytic rates that are up to 200 times higher than those of their normal tissues of origin; this occurs even if oxygen is plentiful.
Otto Warburg postulated that this change in metabolism is the fundamental cause of cancer, a claim now known as the Warburg hypothesis
. Today it is known that mutation
s in oncogene
s and tumor suppressor gene
s are responsible for malignant transformation
; however a fundamental cause of cancer - if there is any - is still not understood.
uptake of 2-18F-2-deoxyglucose
(FDG) (a radioactive modified hexokinase
substrate
) with positron emission tomography
(PET).
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, it has been proposed that cancer cells (and normal proliferating cells) may need to activate glycolysis despite the presence of oxygen in order to proliferate .
There is also evidence that attributes some of the high aerobic glycolytic rates to an overexpressed form of mitochondrially-bound hexokinase
responsible for driving the high glycolytic activity.
In March 2008 Lewis C. Cantley
and colleagues at the Harvard Medical School
announced that they had identified the enzyme
that gave rise to the Warburg Effect. The researchers stated that Tumor M2-PK
, a form of the pyruvate kinase
enzyme, 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 experimented upon. The enzyme variety 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.
(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.
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.
in which the cells producing energy by glycolysis were not the tumor cells, but the stromal fibroblasts. Although it was stated that the Warburg Effect would exist in certain cancer types potentially, it highlighted the need for a closer look at tumor metabolism.
Biochemistry
Biochemistry, sometimes called biological chemistry, is the study of chemical processes in living organisms, including, but not limited to, living matter. Biochemistry governs all living organisms and living processes...
, one in plant physiology
Plant physiology
Plant physiology is a subdiscipline of botany concerned with the functioning, or physiology, of plants. Closely related fields include plant morphology , plant ecology , phytochemistry , cell biology, and molecular biology.Fundamental processes such as photosynthesis, respiration, plant nutrition,...
and the other in oncology
Oncology
Oncology is a branch of medicine that deals with cancer...
, both due to Nobel laureate Otto Heinrich Warburg
Otto Heinrich Warburg
Otto Heinrich Warburg , son of physicist Emil Warburg, was a German physiologist, medical doctor and Nobel laureate. He served as an officer in the elite Uhlan during the First World War and won the Iron Cross for bravery. Warburg was one of the twentieth century's leading biochemists...
.
Plant physiology
In plant physiology, the Warburg effect is the inhibition of carbon dioxideCarbon dioxide
Carbon dioxide is a naturally occurring chemical compound composed of two oxygen atoms covalently bonded to a single carbon atom...
fixation
Carbon fixation
In biology, carbon fixation is the reduction of carbon dioxide to organic compounds by living organisms. The obvious example is photosynthesis. Carbon fixation requires both a source of energy such as sunlight, and an electron donor such as water. All life depends on fixed carbon. Organisms that...
, and subsequently of photosynthesis
Photosynthesis
Photosynthesis is a chemical process that converts carbon dioxide into organic compounds, especially sugars, using the energy from sunlight. Photosynthesis occurs in plants, algae, and many species of bacteria, but not in archaea. Photosynthetic organisms are called photoautotrophs, since they can...
, by high oxygen
Oxygen
Oxygen is the element with atomic number 8 and represented by the symbol O. Its name derives from the Greek roots ὀξύς and -γενής , because at the time of naming, it was mistakenly thought that all acids required oxygen in their composition...
concentrations.
The oxygenase
Oxygenase
An oxygenase is any enzyme that oxidizes a substrate by transferring the oxygen from molecular oxygen O2 to it. The oxygenases form a class of oxidoreductases; their EC number is EC 1.13 or EC 1.14....
activity of RuBisCO
RuBisCO
Ribulose-1,5-bisphosphate carboxylase oxygenase, commonly known by the shorter name RuBisCO, is an enzyme involved in the first major step of carbon fixation, a process by which atmospheric carbon dioxide is converted by plants to energy-rich molecules such as glucose. RuBisCo is an abbreviation...
, which initiates the process of photorespiration
Photorespiration
Photorespiration, or "'photo-respiration'", is a process in plant metabolism by which RuBP has oxygen added to it by the enzyme , instead of carbon dioxide during normal photosynthesis. This is the beginning step of the Calvin-Benson cycle...
, largely accounts for this effect.
Basis
In oncology, the Warburg effect is the observation that most cancerCancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
cells predominantly produce energy by a high rate of glycolysis
Glycolysis
Glycolysis is the metabolic pathway that converts glucose C6H12O6, into pyruvate, CH3COCOO− + H+...
followed by lactic acid fermentation
Lactic acid fermentation
Lactic acid fermentation is a biological process by which sugars such as glucose, fructose, and sucrose, are converted into cellular energy and the metabolic byproduct lactate. It is an anaerobic fermentation reaction that occurs in some bacteria and animal cells, such as muscle cells, in the...
in the cytosol
Cytosol
The cytosol or intracellular fluid is the liquid found inside cells, that is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondrion into compartments....
, rather than by a comparatively low rate of glycolysis followed by oxidation of pyruvate in mitochondria like most normal cells. The latter process is aerobic
Aerobic
Aerobic is a word that means "requiring air", where "air" usually means oxygen.Aerobic may also refer to:* Aerobic exercise, prolonged exercise of moderate intensity* Aerobics, a form of aerobic exercise...
(uses oxygen). Malignant rapidly-growing tumor
Tumor
A tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size. Tumor is not synonymous with cancer...
cells typically have glycolytic rates that are up to 200 times higher than those of their normal tissues of origin; this occurs even if oxygen is plentiful.
Otto Warburg postulated that this change in metabolism is the fundamental cause of cancer, a claim now known as the Warburg hypothesis
Warburg hypothesis
The Warburg effect is the observation that cancer cells exhibit glycolysis with lactate secretion and mitochondrial respiration even in the presence of oxygen....
. Today it is known that mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
s in oncogene
Oncogene
An oncogene is a gene that has the potential to cause cancer. In tumor cells, they are often mutated or expressed at high levels.An oncogene is a gene found in the chromosomes of tumor cells whose activation is associated with the initial and continuing conversion of normal cells into cancer...
s and tumor suppressor gene
Tumor suppressor gene
A tumor suppressor gene, or anti-oncogene, is a gene that protects a cell from one step on the path to cancer. When this gene is mutated to cause a loss or reduction in its function, the cell can progress to cancer, usually in combination with other genetic changes.-Two-hit hypothesis:Unlike...
s are responsible for malignant transformation
Malignant transformation
Malignant transformation is the process by which cells acquire the properties of cancer. This may occur as a primary process in normal tissue, or secondarily as malignant degeneration of a previously existing benign tumor....
; however a fundamental cause of cancer - if there is any - is still not understood.
Use in diagnosis
The Warburg effect has important medical applications, as high aerobic glycolysis by malignant tumors is utilized clinically to diagnose and monitor treatment responses of cancers by imagingChemical imaging
Chemical imaging is the analytical capability to create a visual image of components distribution from simultaneous measurement of spectra and spatial, time informations....
uptake of 2-18F-2-deoxyglucose
Fluorodeoxyglucose
Fludeoxyglucose or fluorodeoxyglucose , commonly abbreviated 18F-FDG or FDG, is a radiopharmaceutical used in the medical imaging modality positron emission tomography...
(FDG) (a radioactive modified hexokinase
Hexokinase
A hexokinase is an enzyme that phosphorylates a six-carbon sugar, a hexose, to a hexose phosphate. In most tissues and organisms, glucose is the most important substrate of hexokinases, and glucose-6-phosphate the most important product....
substrate
Substrate (biochemistry)
In biochemistry, a substrate is a molecule upon which an enzyme acts. Enzymes catalyze chemical reactions involving the substrate. In the case of a single substrate, the substrate binds with the enzyme active site, and an enzyme-substrate complex is formed. The substrate is transformed into one or...
) with positron emission tomography
Positron emission tomography
Positron emission tomography is nuclear medicine imaging technique that produces a three-dimensional image or picture of functional processes in the body. The system detects pairs of gamma rays emitted indirectly by a positron-emitting radionuclide , which is introduced into the body on a...
(PET).
Possible explanations of the effect
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 apoptosisApoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
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, it has been proposed that cancer cells (and normal proliferating cells) may need to activate glycolysis despite the presence of oxygen in order to proliferate .
There is also evidence that attributes some of the high aerobic glycolytic rates to an overexpressed form of mitochondrially-bound hexokinase
Hexokinase
A hexokinase is an enzyme that phosphorylates a six-carbon sugar, a hexose, to a hexose phosphate. In most tissues and organisms, glucose is the most important substrate of hexokinases, and glucose-6-phosphate the most important product....
responsible for driving the high glycolytic activity.
In March 2008 Lewis C. Cantley
Lewis C. Cantley
Lewis C. Cantley is an American cell biologist and biochemist and a professor in the Departments of Systems Biology and Medicine at Harvard Medical School, and the Director of Cancer Research at the Beth Israel Deaconess Medical Center, in Boston, Massachusetts...
and colleagues at the Harvard Medical School
Harvard Medical School
Harvard Medical School is the graduate medical school of Harvard University. It is located in the Longwood Medical Area of the Mission Hill neighborhood of Boston, Massachusetts....
announced that they had identified the enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
that gave rise to the Warburg Effect. The researchers stated that Tumor M2-PK
Tumor M2-PK
Tumor M2-PK is a synonym for the dimeric form of the pyruvate kinase isoenzyme type M2 , a key enzyme within tumor metabolism. Tumor M2-PK can be elevated in many tumor types, rather than being an organ-specific tumor marker such as PSA...
, a form of the pyruvate kinase
Pyruvate kinase
Pyruvate kinase is an enzyme involved in glycolysis. It catalyzes the transfer of a phosphate group from phosphoenolpyruvate to ADP, yielding one molecule of pyruvate and one molecule of ATP.-Reaction:The reaction with pyruvate kinase:...
enzyme, 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 experimented upon. The enzyme variety 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.
Glycolytic Inhibitors
Many substances have been developed which inhibit glycolysis, and such glycolytic inhibitors are currently the subject of intense research as anticancer agents. Some glycolytic inhibitors currently being studied as anticancer treatments include SB-204990, 2-deoxy-D-glucose2-Deoxy-D-glucose
2-Deoxy-D-glucose is a glucose molecule which has the 2-hydroxyl group replaced by hydrogen, so that it cannot undergo further glycolysis. Glucose hexokinase traps this substance in most cells so that it makes a good marker for tissue glucose use and hexokinase activity. Many cancers have elevated...
(2DG), 3-bromopyruvate (3-BrPA, Bromopyruvic acid, or bromopyruvate), 3-BrOP, 5-thioglucose and dichloroacetic acid
Dichloroacetic acid
Dichloroacetic acid, often abbreviated DCA, is the chemical compound with formula . It is an acid, an analogue of acetic acid, in which two of the three hydrogen atoms of the methyl group have been replaced by chlorine atoms. The salts and esters of dichloroacetic acid are called dichloroacetates...
(DCA). Clinical trials are ongoing for 2-DG and DCA.
DCA, a small-molecule inhibitor of mitochondrial pyruvate dehydrogenase kinase
Pyruvate dehydrogenase kinase
Pyruvate dehydrogenase kinase is a kinase enzyme which acts to inactivate the enzyme pyruvate dehydrogenase by phosphorylating it using ATP....
, "downregulates" glycolysis in vitro
In vitro
In vitro refers to studies in experimental biology that are conducted using components of an organism that have been isolated from their usual biological context in order to permit a more detailed or more convenient analysis than can be done with whole organisms. Colloquially, these experiments...
and in vivo
In vivo
In vivo is experimentation using a whole, living organism as opposed to a partial or dead organism, or an in vitro controlled environment. Animal testing and clinical trials are two forms of in vivo research...
. Researchers at the University of Alberta
University of Alberta
The University of Alberta is a public research university located in Edmonton, Alberta, Canada. Founded in 1908 by Alexander Cameron Rutherford, the first premier of Alberta and Henry Marshall Tory, its first president, it is widely recognized as one of the best universities in Canada...
theorized in 2007 that DCA might have therapeutic benefits against many types of cancers.
Alternative models
A model called the Reverse Warburg EffectReverse Warburg Effect
-Introduction:The reverse Warburg effect in human breast cancers was first proposed by Dr. Michael P. Lisanti and colleagues in 2009. According to this model, aerobic glycolysis actually takes place in tumor associated fibroblasts, and not in cancer cells.This has important consequences for tumor...
in which the cells producing energy by glycolysis were not the tumor cells, but the stromal fibroblasts. Although it was stated that the Warburg Effect would exist in certain cancer types potentially, it highlighted the need for a closer look at tumor metabolism.