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

By Jianrong Lu, Ming Tan, Qingsong Cai. Cancer Letters, 2014

719 citations recorded by the source corpus.

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 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.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/c44b41672714b7a403bd929e81202d23337d1548

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In Cancer Research

1. A. Mayer
2. H. Schmidberger
3. Gabriele Multhoff
4. P. Vaupel

In Molecular Biology

1. Gabriele Multhoff
2. P. Vaupel
3. H. Schmidberger
4. A. Mayer

Citations in the corpus

• The Warburg effect: essential part of metabolic reprogramming and central contributor to cancer progression (2019, background): “Although there is unequivocal experimental evidence from in vivo studies against Warburg’s original notion of defective mitochondria in cancer cells, hypotheses similar to Warburg’s ‘Damaged mitochondria model’ are still popular in cancer research based on the discovery of (a) mutations of TCA-cycle”
• Revisiting the Warburg effect: historical dogma versus current understanding (2020, background): “…cells, and (i) maintenance of the pHi–pHe gradient (Semenza, 2010; Cantor & Sabatini, 2012; Martinez-Pastor & Mostolavsky, 2012; Faubert et al. 2013; Lu et al. 2015; Tran et al. 2016; He et al. 2017; Yu et al. 2017; Parks et al. 2017; Kato et al. 2018; Counihan et al. 2018; Tameemi et al.…”