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