Trends in Biochemical Sciences
OpinionSpecial Issue: Mitochondria & MetabolismThe Warburg Effect: How Does it Benefit Cancer Cells?
Section snippets
Glucose Metabolism and the Warburg Effect
The metabolism of glucose, the central macronutrient, allows for energy to be harnessed in the form of ATP (see Glossary) through the oxidation of its carbon bonds. This process is essential for sustaining all mammalian life. In mammals, the end product can be lactate or, upon full oxidation of glucose via respiration in the mitochondria, CO2. In tumors and other proliferating or developing cells, the rate of glucose uptake dramatically increases and lactate is produced, even in the presence of
Historical Perspectives of the Warburg Effect
During the 1920s, Otto Warburg and colleagues made the observation that tumors were taking up enormous amounts of glucose compared with what was seen in the surrounding tissue. Additionally, glucose was fermented to produce lactate even in the presence of oxygen, hence the term ‘aerobic glycolysis’ 1, 2. However, it was also noted that respiration alone could maintain tumor viability. Therefore, it was concluded that, to kill tumor cells by depriving them of energy, both glucose and oxygen had
Warburg Effect and Rapid ATP Synthesis
Per unit of glucose, aerobic glycolysis is an inefficient means of generating ATP compared with the amount obtained by mitochondrial respiration 17, 18. However, the rate of glucose metabolism through aerobic glycolysis is higher, such that the production of lactate from glucose occurs 10–100 times faster than the complete oxidation of glucose in the mitochondria. In fact, the amount of ATP synthesized over any given period of time is comparable when either form of glucose metabolism is
Warburg Effect and Biosynthesis
The Warburg Effect has been proposed to be an adaptation mechanism to support the biosynthetic requirements of uncontrolled proliferation (Figure 2). In this scenario, the increased glucose consumption is used as a carbon source for anabolic processes needed to support cell proliferation 17, 26, 27, 28, 29, 30, 31, 32. This excess carbon is diverted into the multiple branching pathways that emanate from glycolysis, and is used for the generation of nucleotides, lipids, and proteins. One example
Warburg Effect and the Tumor Microenvironment
Separate from the cell-intrinsic functions described in the previous sections, the Warburg Effect may present an advantage for cell growth in a multicellular environment. Acidification of the microenvironment and other metabolic crosstalk are intriguing possibilities. Elevated glucose metabolism decreases the pH in the microenvironment due to lactate secretion (Figure 2) [42]. The potential benefits of acidosis to cancer cells are multifold. An acid-mediated invasion hypothesis suggests that H+
The Warburg Effect and Cell Signaling
We and others have proposed that the Warburg Effect confers direct signaling functions to tumor cells 18, 39, 47, 48, 49. This proposal is particularly attractive since it identifies a direct causal role of altered glucose metabolism in promoting tumorigenesis as a result of this signal transduction affecting other cellular processes. Two areas of signaling function are the generation and modulation of reactive oxygen species (ROS) and the mediation of chromatin state. Other studies have
Concluding Remarks
Extensive research on the Warburg Effect and its functions in cancer cells has advanced our understanding of its causes and requirements for tumor cell proliferation 29, 52. However, we argue that it has left us with a surprising lack of clarity regarding its ontology. These uncertainties should challenge us to better understand its function in promoting tumor growth. It is likely that we will require a better understanding of the biology of Warburg Effect if therapeutic advances are to be made
Acknowledgments
This work was supported by awards from the National Institute of Health (R00CA168997, R01CA193256, and T32GM007273), the National Science Foundation, and the Sloan Foundation. J.W.L. acknowledges Donald McDonnell and numerous other colleagues, notably Lew Cantley, for helpful discussions on the history of the Warburg Effect.
Glossary
- Aerobic glycolysis
- enhanced rate of glycolysis and fermentation to lactate that occurs in the presence of functioning mitochondria.
- ATP
- adenosine triphosphate, cellular energy currency.
- Flux
- the rate of the overall chemical reaction resulting from the conversion of one metabolite to another through a defined metabolic pathway.
- NADH
- reduced nicotinamide adenine dinucleotide (NAD+); a reducing agent involved in redox reactions that is responsible for the transfer of electrons. NADH is a key reducing
References (62)
Growth factors rapidly induce expression of the glucose transporter gene
J. Biol. Chem.
(1988)Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance
Cancer Cell
(2006)An essential role of the mitochondrial electron transport chain in cell proliferation is to enable aspartate synthesis
Cell
(2015)Broad anti-tumor activity of a small molecule that selectively targets the Warburg Effect and lipogenesis
Cancer Cell
(2015)Supporting aspartate biosynthesis is an essential function of respiration in proliferating cells
Cell
(2015)- et al.
Metabolic flux and the regulation of mammalian cell growth
Cell Metab.
(2011) Constant growth rate can be supported by decreasing energy flux and increasing aerobic glycolysis
Cell Rep.
(2014)Metabolic competition in the tumor microenvironment is a driver of cancer progression
Cell
(2015)Phosphoenolpyruvate is a metabolic checkpoint of anti-tumor T cell responses
Cell
(2015)The biology of cancer: metabolic reprogramming fuels cell growth and proliferation
Cell Metab.
(2008)
Hexokinase 2 is required for tumor initiation and maintenance and its systemic deletion is therapeutic in mouse models of cancer
Cancer Cell
Metabolic reprogramming: a cancer hallmark even warburg did not anticipate
Cancer Cell
Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism
Cell
Cellular metabolic stress: considering how cells respond to nutrient excess
Mol. Cell
Posttranscriptional control of T cell effector function by aerobic glycolysis
Cell
Physiological roles of mitochondrial reactive oxygen species
Mol. Cell
The consequences of enhanced cell-autonomous glucose metabolism
Trends Endocrinol. Metab.
Characterization of the usage of the serine metabolic network in human cancer
Cell Rep.
Metabolic regulation of epigenetics
Cell Metab.
Quantitative dynamics of the link between cellular metabolism and histone acetylation
J. Biol. Chem.
Acetyl-CoA induces cell growth and proliferation by promoting the acetylation of histones at growth genes
Mol. Cell
The metabolism of carcinoma cells
J. Cancer Res.
Ueber den stoffwechsel der tumoren
Biochem. Zeitschrift
The metabolism of tumors in the body
J. Gen. Physiol.
Observations on the carbohydrate metabolism of tumours
Biochem. J.
On the origin of cancer cells
Science
Bioenergetics and the problem of tumor growth: an understanding of the mechanism of the generation and control of biological energy may shed light on the problem of tumor growth
Am. Sci.
Stimulation of glycolysis and amino acid uptake in NRK-49F cells by transforming growth factor beta and epidermal growth factor
Proc. Natl. Acad. Sci. U.S.A.
Elevated levels of glucose transport and transporter messenger RNA are induced by ras or src oncogenes
Science
Transformation of rat fibroblasts by FSV rapidly increases glucose transporter gene transcription
Science
A unique glucose-dependent apoptotic pathway induced by c-Myc
Proc. Natl. Acad. Sci. U.S.A.
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