Opinion
Special Issue: Mitochondria & Metabolism
The Warburg Effect: How Does it Benefit Cancer Cells?

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Trends

Both glycolytic and mitochondrial metabolism are essential for cell proliferation in both past and present conceptions of the Warburg Effect.

Numerous proposals for the function of the Warburg Effect have emerged over the years.

Each of the proposed functions of the Warburg Effect is attractive, but also raises questions.

Signal transduction functions for the Warburg Effect appear likely, but are difficult to test experimentally.

Cancer cells rewire their metabolism to promote growth, survival, proliferation, and long-term maintenance. The common feature of this altered metabolism is the increased glucose uptake and fermentation of glucose to lactate. This phenomenon is observed even in the presence of completely functioning mitochondria and, together, is known as the ‘Warburg Effect’. The Warburg Effect has been documented for over 90 years and extensively studied over the past 10 years, with thousands of papers reporting to have established either its causes or its functions. Despite this intense interest, the function of the Warburg Effect remains unclear. Here, we analyze several proposed explanations for the function of Warburg Effect, emphasize their rationale, and discuss their controversies.

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)

  • K.C. Patra

    Hexokinase 2 is required for tumor initiation and maintenance and its systemic deletion is therapeutic in mouse models of cancer

    Cancer Cell

    (2013)
  • P.S. Ward et al.

    Metabolic reprogramming: a cancer hallmark even warburg did not anticipate

    Cancer Cell

    (2012)
  • H. Ying

    Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism

    Cell

    (2012)
  • K.E. Wellen et al.

    Cellular metabolic stress: considering how cells respond to nutrient excess

    Mol. Cell

    (2010)
  • C-H. Chang

    Posttranscriptional control of T cell effector function by aerobic glycolysis

    Cell

    (2013)
  • L.A. Sena et al.

    Physiological roles of mitochondrial reactive oxygen species

    Mol. Cell

    (2012)
  • J.W. Locasale

    The consequences of enhanced cell-autonomous glucose metabolism

    Trends Endocrinol. Metab.

    (2012)
  • M. Mehrmohamadi

    Characterization of the usage of the serine metabolic network in human cancer

    Cell Rep.

    (2014)
  • C. Lu et al.

    Metabolic regulation of epigenetics

    Cell Metab.

    (2012)
  • A.G. Evertts

    Quantitative dynamics of the link between cellular metabolism and histone acetylation

    J. Biol. Chem.

    (2013)
  • L. Cai

    Acetyl-CoA induces cell growth and proliferation by promoting the acetylation of histones at growth genes

    Mol. Cell

    (2011)
  • O. Warburg

    The metabolism of carcinoma cells

    J. Cancer Res.

    (1925)
  • O. Warburg

    Ueber den stoffwechsel der tumoren

    Biochem. Zeitschrift

    (1924)
  • O. Warburg

    The metabolism of tumors in the body

    J. Gen. Physiol.

    (1927)
  • H.G. Crabtree

    Observations on the carbohydrate metabolism of tumours

    Biochem. J.

    (1929)
  • O. Warburg

    On the origin of cancer cells

    Science

    (1956)
  • E. Racker

    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.

    (1972)
  • P. Boerner

    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.

    (1985)
  • J.S. Flier

    Elevated levels of glucose transport and transporter messenger RNA are induced by ras or src oncogenes

    Science

    (1987)
  • M.J. Birnbaum

    Transformation of rat fibroblasts by FSV rapidly increases glucose transporter gene transcription

    Science

    (1987)
  • H. Shim

    A unique glucose-dependent apoptotic pathway induced by c-Myc

    Proc. Natl. Acad. Sci. U.S.A.

    (1998)
  • Cited by (0)

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