The Warburg effect in tumor progression: Mitochondrial oxidative metabolism as an anti-metastasis mechanism

doi:10.1016/j.canlet.2014.04.001

Cancer Letters

Volume 356, Issue 2, Part A, 28 January 2015, Pages 156-164

https://doi.org/10.1016/j.canlet.2014.04.001 Get rights and content

Abstract

Compared to normal cells, cancer cells strongly upregulate glucose uptake and glycolysis to give rise to increased yield of intermediate glycolytic metabolites and the end product pyruvate. Moreover, glycolysis is uncoupled from the mitochondrial tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS) in cancer cells. Consequently, the majority of glycolysis-derived pyruvate is diverted to lactate fermentation and kept away from mitochondrial oxidative metabolism. This metabolic phenotype is known as the Warburg effect. While it has become widely accepted that the glycolytic intermediates provide essential anabolic support for cell proliferation and tumor growth, it remains largely elusive whether and how the Warburg metabolic phenotype may play a role in tumor progression. We hereby review the cause and consequence of the restrained oxidative metabolism, in particular in the context of tumor metastasis. Cells change or lose their extracellular matrix during the metastatic process. Inadequate/inappropriate matrix attachment generates reactive oxygen species (ROS) and causes a specific type of cell death, termed anoikis, in normal cells. Although anoikis is a barrier to metastasis, cancer cells have often acquired elevated threshold for anoikis and hence heightened metastatic potential. As ROS are inherent byproducts of oxidative metabolism, forced stimulation of glucose oxidation in cancer cells raises oxidative stress and restores cells’ sensitivity to anoikis. Therefore, by limiting the pyruvate flux into mitochondrial oxidative metabolism, the Warburg effect enables cancer cells to avoid excess ROS generation from mitochondrial respiration and thus gain increased anoikis resistance and survival advantage for metastasis. Consistent with this notion, pro-metastatic transcription factors HIF and Snail attenuate oxidative metabolism, whereas tumor suppressor p53 and metastasis suppressor KISS1 promote mitochondrial oxidation. Collectively, these findings reveal mitochondrial oxidative metabolism as a critical suppressor of metastasis and justify metabolic therapies for potential prevention/intervention of tumor metastasis.

Section snippets

Introduction: the Warburg effect in cancer

Altered metabolism is a universal property of most, if not all, cancer cells [1], [2]. One of the first identified and most common biochemical characteristics of cancer cells is aberrant glucose metabolism. Glucose is a main source of energy and carbon for mammalian cells, providing not only energy (ATP) but also metabolites for various anabolic pathways [3]. Glucose is taken up into the cell by glucose transporters and metabolized to pyruvate in the cytosol through a multi-step process known

Is glucose oxidation incompatible with high glycolysis in cancer cells?

One reason that cancer cells limit oxidative metabolism of glucose may be that it is not compatible with high rates of glycolysis. The TCA cycle is a hub of metabolism, with central importance in both energy production and biosynthesis. Cells must control the TCA cycle to regulate energy balance and TCA metabolite levels in the mitochondria. This regulation is fulfilled by feedback inhibition. As an important part of metabolism, metabolic flux through the glycolytic pathway is tightly regulated

Is glucose oxidation limited because high glycolysis relies on NAD+ regenerated from increased lactate conversion?

Glycolysis is a catabolic pathway that consumes nicotinamide adenine dinucleotide (NAD+). In glycolysis, oxidation of glyceraldehyde 3-phosphate requires NAD+ as an electron acceptor--it converts to NADH. This step is catalyzed by glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and NAD+ is a mandatory coenzyme. A recent study shows that reduced availability of NAD+ attenuates glycolysis at the GAPDH step, resulting in the accumulation of glycolytic intermediates before this step and a decrease

Control of glucose oxidation by PDH and PDKs

At the center of glucose oxidative metabolism lies the multisubunit PDH complex. PDH complex commits pyruvate into the TCA cycle by catalyzing the rate-limiting oxidative decarboxylation of pyruvate into acetyl-CoA. It interconnects glycolysis and the TCA cycle, thus representing a key regulatory step in glucose metabolism. The activity of PDH is tightly regulated by a variety of allosteric effectors and by reversible phosphorylation. PDH complex E1α subunit can be phosphorylated by PDH kinases

Metabolic control of anoikis in normal cells

Metabolism is intrinsically linked to cell death, as mitochondria play a central role in both energy metabolism and apoptosis [28]. Mitochondrial intermembranous space (IMS) contains key pro-apoptotic factors, such as cytochrome c, which trigger apoptosis if released into the cytosol. A specific type of apoptosis, termed anoikis, is induced by loss of cell-matrix interaction [29]. Survival of normal cells relies on integrin-mediated attachment to the extracellular matrix that elicits

The Warburg effect contributes to anoikis resistance and metastasis

The development of metastasis is a complex process including detachment of tumor cells from the primary site, local invasion and migration, intravasation, survival in the circulation, extravasation, and colonization of the secondary sites. During the process, cells are displaced from their natural matrix niche or completely deprived of matrix support (during circulation). Therefore, resistance to anoikis is a prerequisite for tumor metastasis.

In contrast to normal cells that are sensitive to

Metastasis regulators impact oxidative metabolism

As discussed in many excellent reviews [1], [3], [50], many well-established oncogenes and tumor suppressors, such as hypoxia-inducible factor (HIF), Akt, Myc, and p53, exert direct impact on metabolism, most notably on glucose uptake and glycolysis. However, increased glycolysis does not evenly increase downstream metabolic pathways (Fig. 1). In particular, pyruvate is preferentially diverted to lactate fermentation, with very little to the mitochondrial TCA cycle. The regulatory mechanisms

Metabolic modulation for anti-metastasis therapy

The Warburg effect not only fuels tumor growth but also facilitates metastatic progression. Current studies position the Warburg effect as a central player in malignancy. Metastasis is the primary cause of cancer mortality. Discovery of its root in altered metabolism may expose its vulnerability, making metabolic modulation a viable therapeutic anti-metastasis approach. An important step towards metabolic therapy is to identify and manipulate critical biochemical nodes that are deregulated in

Conflict of Interest

None.

Acknowledgement

This work was supported by NIH Grants R01CA137021 (to J.L.) and R01CA149646 (to M.T.).

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Mini-reviewThe Warburg effect in tumor progression: Mitochondrial oxidative metabolism as an anti-metastasis mechanism

Abstract

Section snippets

Introduction: the Warburg effect in cancer

Is glucose oxidation incompatible with high glycolysis in cancer cells?

Is glucose oxidation limited because high glycolysis relies on NAD+ regenerated from increased lactate conversion?

Control of glucose oxidation by PDH and PDKs

Metabolic control of anoikis in normal cells

The Warburg effect contributes to anoikis resistance and metastasis

Metastasis regulators impact oxidative metabolism

Metabolic modulation for anti-metastasis therapy

Conflict of Interest

Acknowledgement

Cancer Cell

Cell

Biochim. Biophys. Acta

Cell Metab.

Cell Metab.

J. Biol. Chem.

Trends Endocrinol. Metab.

Cell Metab.

Cell Metab.

Adv. Enzyme Regul.

Mol. Cell

Curr. Opin. Cell Biol.

Mol. Cell

Am. J. Pathol.

Cancer Lett.

Mol. Cell

Mol. Cell

J. Biol. Chem.

Cell

Cell Metab.

Cell Metab.

Cell Metab.

Cell

Cancer Cell

Cell

Cell Metab.

Cell

Eur. J. Cancer

Cancer Cell

Understanding the Warburg effect: the metabolic requirements of cell proliferation

Science

Otto Warburg’s contributions to current concepts of cancer metabolism

Nat. Rev. Cancer

Contribution by different fuels and metabolic pathways to the total ATP turnover of proliferating MCF-7 breast cancer cells

Biochem. J.

Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis

Proc. Natl. Acad. Sci. USA

Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction

Proc. Natl. Acad. Sci. USA

Aerobic glycolysis: meeting the metabolic requirements of cell proliferation

Annu. Rev. Cell Dev. Biol.

Metabolic pathway alterations that support cell proliferation

Cold Spring Harb. Symp. Quant. Biol.

On getting there from here

Science

Evolution of allosteric citrate binding sites on 6-phosphofructo-1-kinase

PLoS One

Alterations in the activity and isozymic profile of human phosphofructokinase during malignant transformation in vivo and in vitro: transformation- and progression-linked discriminants of malignancy

Cancer Res.

Subunit composition, regulatory properties, and phosphorylation of phosphofructokinase from human gliomas

Cancer Res.

High expression of inducible 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (iPFK-2; PFKFB3) in human cancers

Cancer Res.

The nicotinamide phosphoribosyltransferase: a molecular link between metabolism, inflammation, and cancer

Cancer Res.

Nampt/PBEF/visfatin and cancer

Cancer Biol. Ther.

Regulation of the pyruvate dehydrogenase complex

Biochem. Soc. Trans.

Transcriptional regulation of pyruvate dehydrogenase kinase

Diabetes Metab. J.

Role of pyruvate dehydrogenase kinase isoenzyme 4 (PDHK4) in glucose homoeostasis during starvation

Biochem. J.

Anoikis

Cell Death Differ.

Mini-review
The Warburg effect in tumor progression: Mitochondrial oxidative metabolism as an anti-metastasis mechanism