Warburg hypothesis
Encyclopedia
The Warburg effect
is the observation that cancer cells exhibit glycolysis with lactate secretion and mitochondrial respiration even in the presence of oxygen.
Warburg's hypothesis was postulated by the Nobel laureate Otto Heinrich Warburg
in 1924. He hypothesized that cancer
, malignant growth, and tumor
growth are caused by the fact that tumor cells mainly generate energy
(as e.g. adenosine triphosphate
/ ATP) by non-oxidative breakdown of glucose
(a process called glycolysis
). This is in contrast to "healthy" cells which mainly generate energy from oxidative breakdown of pyruvate. Pyruvate is an end-product of glycolysis
, and is oxidized within the mitochondria. Hence, according to Warburg, cancer should be interpreted as a mitochondrial dysfunction. Warburg reported a fundamental difference between normal and cancerous cells to be the ratio of glycolysis to respiration; this observation is also known as the Warburg effect
.
Cancer is caused by mutation
s and altered gene expression, in a process called malignant transformation
, resulting in an uncontrolled growth of cells. The metabolic differences observed by Warburg adapts cancer cells to the hypoxic
(oxygen-deficient) conditions inside solid tumors, and results largely from the same mutations in oncogenes and tumor suppressor genes that cause the other abnormal characteristics of cancer cells. Therefore, the metabolic change observed by Warburg is not so much the cause of cancer, as he claimed, but rather, it is one of the characteristic effects of cancer-causing mutations.
Warburg articulated his hypothesis in a paper entitled The Prime Cause and Prevention of Cancer which he presented in lecture at the meeting of the Nobel-Laureates on June 30, 1966 at Lindau
, Lake Constance
, Germany. In this speech, Warburg presented evidence in support of the claim that anaerobiosis
was a primary cause of cancerous cells. Put in his own words, "the prime cause of cancer is the replacement of the respiration of oxygen in normal body cells by a fermentation of sugar."
In recent years, Warburg's hypothesis has re-gained attention due to several discoveries linking impaired mitochondrial function as well as impaired respiration to the growth, division and expansion of tumor cells. In a study by Michael Ristow
and co-workers, colon cancer lines were modified to overexpress frataxin
. The results of their work suggest that an increase in oxidative metabolism induced by mitochondrial frataxin may inhibit cancer growth in mammals.
Subsequent work has shown that the Warburg effect, indeed, might lead to a promising approach in the treatment of solid tumors. The chemical dichloroacetic acid
(DCA), which promotes respiration and the activity of mitochondria, has been shown to kill cancer cells in vitro and in some animal models. The body often kills damaged cells by apoptosis
, a mechanism of self-destruction that involves mitochondria, but this mechanism fails in cancer cells where the mitochondria are shut down. The reactivation of mitochondria in cancer cells restarts their apoptosis program. Besides promising human research at the Department of Medicine, University of Alberta
led by Dr Evangelos Michelakis, other glycotic inhibitors besides DCA that hold promise include 3-BrOP being researched at The University of Texas M. D. Anderson Cancer Center, 2-deoxyglucose (2-DG) at Emory University
School of Medicine, and lactate dehydrogenase A at Johns Hopkins University
.
Warburg effect
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.-Plant physiology:...
is the observation that cancer cells exhibit glycolysis with lactate secretion and mitochondrial respiration even in the presence of oxygen.
Warburg's hypothesis was postulated by the 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...
in 1924. He hypothesized that cancer
Cancer
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...
, malignant growth, and 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...
growth are caused by the fact that tumor cells mainly generate energy
Energy
In physics, energy is an indirectly observed quantity. It is often understood as the ability a physical system has to do work on other physical systems...
(as e.g. adenosine triphosphate
Adenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...
/ ATP) by non-oxidative breakdown of glucose
Glucose
Glucose is a simple sugar and an important carbohydrate in biology. Cells use it as the primary source of energy and a metabolic intermediate...
(a process called glycolysis
Glycolysis
Glycolysis is the metabolic pathway that converts glucose C6H12O6, into pyruvate, CH3COCOO− + H+...
). This is in contrast to "healthy" cells which mainly generate energy from oxidative breakdown of pyruvate. Pyruvate is an end-product of glycolysis
Glycolysis
Glycolysis is the metabolic pathway that converts glucose C6H12O6, into pyruvate, CH3COCOO− + H+...
, and is oxidized within the mitochondria. Hence, according to Warburg, cancer should be interpreted as a mitochondrial dysfunction. Warburg reported a fundamental difference between normal and cancerous cells to be the ratio of glycolysis to respiration; this observation is also known as the Warburg effect
Warburg effect
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.-Plant physiology:...
.
Cancer is caused by 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 and altered gene expression, in a process called 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....
, resulting in an uncontrolled growth of cells. The metabolic differences observed by Warburg adapts cancer cells to the hypoxic
Hypoxia (medical)
Hypoxia, or hypoxiation, is a pathological condition in which the body as a whole or a region of the body is deprived of adequate oxygen supply. Variations in arterial oxygen concentrations can be part of the normal physiology, for example, during strenuous physical exercise...
(oxygen-deficient) conditions inside solid tumors, and results largely from the same mutations in oncogenes and tumor suppressor genes that cause the other abnormal characteristics of cancer cells. Therefore, the metabolic change observed by Warburg is not so much the cause of cancer, as he claimed, but rather, it is one of the characteristic effects of cancer-causing mutations.
Warburg articulated his hypothesis in a paper entitled The Prime Cause and Prevention of Cancer which he presented in lecture at the meeting of the Nobel-Laureates on June 30, 1966 at Lindau
Lindau
Lindau is a Bavarian town and an island on the eastern side of Lake Constance, the Bodensee. It is the capital of the Landkreis or rural district of Lindau. The historic city of Lindau is located on an island which is connected with the mainland by bridge and railway.- History :The name Lindau was...
, Lake Constance
Lake Constance
Lake Constance is a lake on the Rhine at the northern foot of the Alps, and consists of three bodies of water: the Obersee , the Untersee , and a connecting stretch of the Rhine, called the Seerhein.The lake is situated in Germany, Switzerland and Austria near the Alps...
, Germany. In this speech, Warburg presented evidence in support of the claim that anaerobiosis
Fermentation (biochemistry)
Fermentation is the process of extracting energy from the oxidation of organic compounds, such as carbohydrates, using an endogenous electron acceptor, which is usually an organic compound. In contrast, respiration is where electrons are donated to an exogenous electron acceptor, such as oxygen,...
was a primary cause of cancerous cells. Put in his own words, "the prime cause of cancer is the replacement of the respiration of oxygen in normal body cells by a fermentation of sugar."
In recent years, Warburg's hypothesis has re-gained attention due to several discoveries linking impaired mitochondrial function as well as impaired respiration to the growth, division and expansion of tumor cells. In a study by Michael Ristow
Michael Ristow
Michael Ristow is a German medical researcher who has published influential articles on the metabolic basis of human diseases, including type 2 diabetes, obesity and cancer, as well as general aging processes...
and co-workers, colon cancer lines were modified to overexpress frataxin
Frataxin
Frataxin is a protein that in humans is encoded by the FXN gene.Frataxin is localized to the mitochondrion. The function of frataxin is not entirely clear, but it seems to be involved in assembly of iron-sulfur clusters...
. The results of their work suggest that an increase in oxidative metabolism induced by mitochondrial frataxin may inhibit cancer growth in mammals.
Subsequent work has shown that the Warburg effect, indeed, might lead to a promising approach in the treatment of solid tumors. The chemical 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), which promotes respiration and the activity of mitochondria, has been shown to kill cancer cells in vitro and in some animal models. The body often kills damaged cells by apoptosis
Apoptosis
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...
, a mechanism of self-destruction that involves mitochondria, but this mechanism fails in cancer cells where the mitochondria are shut down. The reactivation of mitochondria in cancer cells restarts their apoptosis program. Besides promising human research at the Department of Medicine, 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...
led by Dr Evangelos Michelakis, other glycotic inhibitors besides DCA that hold promise include 3-BrOP being researched at The University of Texas M. D. Anderson Cancer Center, 2-deoxyglucose (2-DG) at Emory University
Emory University
Emory University is a private research university in metropolitan Atlanta, located in the Druid Hills section of unincorporated DeKalb County, Georgia, United States. The university was founded as Emory College in 1836 in Oxford, Georgia by a small group of Methodists and was named in honor of...
School of Medicine, and lactate dehydrogenase A at Johns Hopkins University
Johns Hopkins University
The Johns Hopkins University, commonly referred to as Johns Hopkins, JHU, or simply Hopkins, is a private research university based in Baltimore, Maryland, United States...
.
See also
- 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...
- CarcinogenCarcinogenA carcinogen is any substance, radionuclide, or radiation that is an agent directly involved in causing cancer. This may be due to the ability to damage the genome or to the disruption of cellular metabolic processes...
- 2-Deoxy-D-glucose2-Deoxy-D-glucose2-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...
- Ketogenic dietKetogenic dietThe ketogenic diet is a high-fat, adequate-protein, low-carbohydrate diet that in medicine is used primarily to treat difficult-to-control epilepsy in children. The diet mimics aspects of starvation by forcing the body to burn fats rather than carbohydrates...
- Pyruvic acidPyruvic acidPyruvic acid is an organic acid, a ketone, as well as the simplest of the alpha-keto acids. The carboxylate ion of pyruvic acid, CH3COCOO−, is known as pyruvate, and is a key intersection in several metabolic pathways....
- Cellular respirationCellular respirationCellular respiration is the set of the metabolic reactions and processes that take place in the cells of organisms to convert biochemical energy from nutrients into adenosine triphosphate , and then release waste products. The reactions involved in respiration are catabolic reactions that involve...
Further reading
- Glycolytic enzyme inhibitors as novel anti-cancer drugs (3-bromopyruvate (3BP) and iodoacetateIodoacetateIodoacetic acid is a derivative of acetic acid. It is a toxic compound, because, like many alkyl halides, it is an alkylating agent. It reacts with cysteine residues in proteins...
(IAA)), James C.K. Lai et al., Idaho State, June 2007 - Can a High-Fat Diet Beat Cancer? by Richard Friebe, Time magazine, Monday, Sep. 17, 2007,
- Can Ancient Herbs Treat Cancer? Time magazine, October 15, 2007 (describes the drug trial of BZL101, a compound from the Scutellaria Barbata herb that prevents cancerous cells from undergoing glycolysisGlycolysisGlycolysis is the metabolic pathway that converts glucose C6H12O6, into pyruvate, CH3COCOO− + H+...
).