Kenyataan
Otto Heinrich Warburg
The Nobel Prize in Physiology or Medicine 1931
Otto Warburg
Otto Warburg
Born: 8 October
1883, Freiburg im Breisgau, Germany
Died: 1 August 1970, West Berlin, West Germany (now
Germany)
Affiliation at the time of the award: Kaiser-Wilhelm-Institut (now
Max-Planck-Institut) für Biologie, Berlin-Dahlem, Germany
Prize motivation: "for his discovery of the nature and
mode of action of the respiratory enzyme"
Field: cell
physiology, metabolism
Prize share: 1/1
Work
In our cells nutrients are broken down so
that energy is released for the construction of cells. This respiration
requires enzymes, substances that facilitate the process without being
incorporated in the final products. Otto Warburg studied the respiration of sea
urchins and other organisms at an early stage of development. By measuring
oxygen consumption in living cells and studying which enzymes reacted, in 1928
he concluded that the respiration enzyme he was looking for was a red ferrous
pigment related to the blood pigment, hemoglobin.
While working at the Marine Biological
Station, Warburg performed research on oxygen consumption in sea
urchin eggs
after fertilization, and
proved that upon fertilization, the rate of respiration increases by as much as
sixfold. His experiments also proved iron is essential for the development of
the larval stage.
In 1918, Warburg was appointed
professor at the Kaiser Wilhelm Institute for
Biology in
Berlin-Dahlem (part of the Kaiser-Wilhelm-Gesellschaft). By
1931 he was named director of the Kaiser Wilhelm Institute
for Cell Physiology, which was founded the previous year by a donation of the Rockefeller Foundation to the Kaiser Wilhelm Gesellschaft (since
renamed the Max Planck Society).
Warburg investigated the
metabolism of tumors and the respiration of cells, particularly cancer cells,
and in 1931 was awarded the Nobel Prize in Physiology for his "discovery of the nature and
mode of action of the respiratory enzyme".[1] The award came after receiving 46
nominations over a period of nine years beginning in 1923, 13 of which were
submitted in 1931, the year he won the prize.[3]
Nobel Laureate George
Wald, having completed his Ph.D. in zoology at Columbia University,
received an award from the US National Research Council to study with Warburg.
During his time with Warburg, 1932-1933, Wald discovered vitamin A in the
retina.
Cancer
Hypotheses
Warburg hypothesized that cancer growth is caused by tumor cells generating energy (as e.g. adenosine triphosphate / ATP) mainly by anaerobic breakdown of glucose (known as fermentation, or anaerobic respiration). 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, and according to Warburg, cancer should be interpreted as a mitochondrial dysfunction.
Cancer, above all other
diseases, has countless secondary causes. But, even for cancer, there is only
one prime cause. Summarized in a few words, the prime cause of cancer is the
replacement of the respiration of oxygen in normal body cells by a fermentation
of sugar.
Warburg continued to develop
the hypothesis experimentally, and gave several prominent lectures outlining
the theory and the data.[14]
Today, mutations in oncogenes and tumor suppressor genes are thought to be responsible for malignant transformation, and
the metabolic
changes are
considered to be a result of these mutations rather than a cause.[15]
The Warburg hypothesis (/ˈvɑːrbʊərɡ/), sometimes known as the Warburg theory of cancer,
postulates that the driver of tumorigenesis is an insufficient cellular
respiration caused by insult to mitochondria.[1] The term Warburg
effect describes
the observation that cancer cells, and many cells grown in-vitro, exhibit
glucose fermentation even when enough oxygen is present to properly respire. In
other words, instead of fully respiring in the presence of adequate oxygen,
cancer cells ferment. The Warburg hypothesis was that the Warburg effect was
the root cause of cancer. The current popular opinion is that cancer cells
ferment glucose while keeping up the same level of respiration that was present
before the process of carcinogenesis, and thus the Warburg effect would be
defined as the observation that cancer cells exhibit glycolysis with lactate
secretion and mitochondrial respiration even in the presence of oxygen.[2]
Warburg's hypothesis was
postulated by the Nobel laureate Otto Heinrich Warburg in 1924.[3] 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, the driver of cancer cells should be interpreted
as stemming from a lowering of mitochondrial respiration. 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 mutations and altered gene expression, in a process
called malignant transformation,
resulting in an uncontrolled growth of cells.[4][5] 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.[6] 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 additional evidence
supporting his theory that the elevated anaerobiosis seen in cancer cells was a consequence of
damaged or insufficient respiration. 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."[7]
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.[8]
Studies published since 2005
have shown that the Warburg effect, indeed, might lead to a promising approach
in the treatment of solid tumors. Alpha-cyano-4-hydroxycinnamic acid
(ACCA;CHCA), 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.[9][10][11][12] Higher affinity MCT inhibitors have been
developed and are currently undergoing clinical trials by Astra-Zeneca.[13] The chemical dichloroacetic acid (DCA),
which promotes respiration and the activity of mitochondria, has also been
shown to kill cancer cells in
vitro and in some animal
models.[14] 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.[15] 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 Bromopyruvic
acid 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 [16] at Johns Hopkins University
School of Medicine.
In plant physiology, the Warburg's effect is the decrease in the rate of photosynthesis by high oxygen concentrations.[1][2] 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.[3]
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,[4][5] rather than by a comparatively low rate of
glycolysis followed by oxidation of pyruvate in mitochondria as in most normal cells.[6][7][8] 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,[9] 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.[10][11]
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.[12] Evidence attributes some of the high
aerobic glycolytic rates to an overexpressed form of mitochondrially-bound hexokinase[13] 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.[14]
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.[15][16]
Glycolytic
inhibitors
Many substances have been
developed which inhibit glycolysis, and such inhibitors are currently the
subject of intense research as anticancer agents,[17] 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.[18]
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.[19][20][21][22]Higher
affinity MCT inhibitors have been developed and are currently undergoing
clinical trials by Astra-Zeneca.[23]
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.[24][25]
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.[26]
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.[27][28]
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
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.[29]
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