The Warburg effect and mitochondrial stability in cancer cells

doi:10.1016/j.mam.2009.12.004

Molecular Aspects of Medicine

Volume 31, Issue 1, February 2010, Pages 60-74

https://doi.org/10.1016/j.mam.2009.12.004 Get rights and content

Abstract

The last decade has witnessed a renaissance of Otto Warburg’s fundamental hypothesis, which he put forward more than 80 years ago, that mitochondrial malfunction and subsequent stimulation of cellular glucose utilization lead to the development of cancer. Since most tumor cells demonstrate a remarkable resistance to drugs that kill non-malignant cells, the question has arisen whether such resistance might be a consequence of the abnormalities in tumor mitochondria predicted by Warburg. The present review discusses potential mechanisms underlying the upregulation of glycolysis and silencing of mitochondrial activity in cancer cells, and how pharmaceutical intervention in cellular energy metabolism might make tumor cells more susceptible to anti-cancer treatment.

Section snippets

Introduction: The Warburg effect vs. the Pasteur effect – historical background and current views

In 1926, Otto Warburg reported that cancer cells produce most of their ATP via glycolysis, also under aerobic conditions (Warburg, 1926). This finding contradicted the Pasteur effect, named after Louis Pasteur, who found that in most mammalian cells the rate of glycolysis decreases significantly in the presence of oxygen. Glycolytic production of ATP under aerobic conditions, the Warburg effect, was found to be a characteristic of most cancer cells, and this finding was confirmed in various

The Crabtree effect

Low mitochondrial contribution to cellular ATP production is not a characteristic of tumor cells only, but is also observed in a variety of fast-growing normal cells (Wang et al., 1976). One of the first demonstrations of inhibition of mitochondrial respiration by stimulated glycolysis, a phenomenon known as the Crabtree effect (reviewed in (Ibsen, 1961)), was made in cells with approximately equal glycolytic and respiratory capacities for ATP synthesis. Thus, the Crabtree effect is absent in

Consequences of the glycolytic switch in tumors

The main reason for the glycolytic shift in cancer cells is assumed to be an inadequate supply of oxygen (Gatenby and Gillies, 2007, Lopez-Lazaro, 2008). Surprisingly, however, tumor cells remain glycolytic also after restoration of the oxygen supply. In fact, the amount of glucose taken up by cancer cells exceeds their bioenergetic demand. It has been suggested that the excessive glycolysis in tumors is required to support cell growth (Vander Heiden et al., 2009). Thus, the end-product of

The role of Bcl-2 proteins in OMM permeabilization

OMM permeabilization engages pro-apoptotic members of the Bcl-2 family of proteins. The first indication that genes and proteins, which play a role in tumorigenesis, might be involved in the negative regulation of cell death came from the finding that the Bcl-2 protein is overexpressed as a result of a chromosomal translocation in B cell lymphomas (Tsujimoto et al., 1987). Overexpression of this protein was shown to inhibit cell death induced by different treatments, such as IL-3 deprivation,

Suppression of the glycolytic pathway

The increased dependence of cancer cells on glycolysis offers a rationale for the design of therapeutic strategies to selectively kill cancer cells by inhibition of the glycolytic pathway. This strategy might be most useful in cells with mitochondrial defects, or under hypoxic conditions when glycolysis is the predominant source of ATP, and the mitochondrial contribution to cellular bioenergetics is minimal. Under such circumstances, inhibition of glycolysis would be expected to severely

Concluding remarks

Despite the heterogeneity of tumors, which dictates an individual approach to anti-cancer treatment, almost all of them demonstrate enhanced uptake and utilization of glucose, a phenomenon known as the Warburg effect. One of the consequences of the upregulation of glycolysis in tumors is stabilization of the mitochondria and increased resistance to OMM permeabilization and apoptotic cell death. Successful elimination of cancer cells is therefore based on the ability of anti-cancer treatment to

Acknowledgements

Work in the authors’ laboratory was supported by grants from the Swedish and Stockholm Cancer Societies, the Swedish Childhood Cancer Foundation, the Swedish Research Council, the EC-FP-6 (Oncodeath and Chemores) and EC-FP-7 (APO-SYS) programs. We apologize to authors whose primary references could not be cited owing to space limitations.

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ReviewThe Warburg effect and mitochondrial stability in cancer cells

Abstract

Section snippets

Introduction: The Warburg effect vs. the Pasteur effect – historical background and current views

The Crabtree effect

Consequences of the glycolytic switch in tumors

The role of Bcl-2 proteins in OMM permeabilization

Suppression of the glycolytic pathway

Concluding remarks

Acknowledgements

Eur. J. Cancer

Cell

Cell

FEBS Lett.

J. Biol. Chem.

Cancer Cell.

Cell

Cell

Int. J. Biochem. Cell Biol.

FEBS Lett.

Biochim. Biophys. Acta

Exp. Cell Res.

Cancer Cell.

Arch. Biochem. Biophys.

Gene

Mol. Cell

Cell Metab.

Cancer Lett.

J. Biol. Chem.

Exp. Cell Res.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Mol. Cell

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Semin. Cancer Biol.

Free Radic. Biol. Med.

Cell Metab.

Clin. Chim Acta

J. Biol. Chem.

J. Biol. Chem.

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Nature

Mitochondrial metabolism of reactive oxygen species

Biochemistry (Mosc)

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Biochem. J.

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J. Biochem.

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Eur. J. Biochem.

Adenine nucleotide translocase-1, a component of the permeability transition pore, can dominantly induce apoptosis

J. Cell Biol.

Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma

Science

Reactive oxygen species in oncogenic transformation

Biochem. Soc. Trans.

Rapid accumulation of Akt in mitochondria following phosphatidylinositol 3-kinase activation

J. Neurochem.

Aerobic glycolysis by proliferating cells: a protective strategy against reactive oxygen species

Faseb J.

A large Ca2+-dependent channel formed by recombinant ADP/ATP carrier from Neurospora crassa resembles the mitochondrial permeability transition pore

Biochemistry

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Mol. Gen. Genet.

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Adv. Exp. Med. Biol.

Dichloroacetate (DCA) sensitizes both wild-type and over expressing Bcl-2 prostate cancer cells in vitro to radiation

Prostate

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Cancer Chemother. Pharmacol.

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J. Bioenerg. Biomembr.

Direct activation of Bax by p53 mediates mitochondrial membrane permeabilization and apoptosis

Science

Review
The Warburg effect and mitochondrial stability in cancer cells