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

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 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.

Efficacy of a ketogenic diet with concomitant intranasal perillyl alcohol as a novel strategy for the therapy of recurrent glioblastoma

“…This so-called Warburg effect (aerobic glycolysis) leads to the increased consumption of glucose and the inability of the affected cells to utilize ketone bodies as an energy source (21). In response to KD, it is hypothesized that tumor cells will starve, or revert to normal mitochondrial activity and respiration, altogether resulting in decreased proliferation and metastatic ability, along with a heightened sensitivity to chemotherapy (22)(23)(24).…”

Bioenergetic adaptations in chemo-resistant ovarian cancer cells

“…showed that the ability to survive under anchorage-independent conditions, a prerequisite for metastatic spread, was higher in glycolytic ovarian cells compared to those with a more aerobic phenotype. Use of the glycolysis pathway allows for less production of ROS, by avoiding excess ROS generation from oxidative respiration 6 . ROS has been associated with development of cellular senescence, which can cause growth arrest and apoptosis [45][46][47] .…”

“…The alterations and adaptions of the glycolytic pathway have been shown to occur at multiple levels including overexpression of glycolytic enzymes, defects in the OXPHOS machinery or oncogenic transformations 4,5 . Increased glucose consumption in cancer cells is devoted to lactate conversion and is uncoupled from oxidative metabolism 6 . Glycolysis and lactate are not only required as fuel sources, but the glycolytic breakdown of glucose also produces various intermediate metabolites that are utilized in anabolic pathways namely pentose phosphate pathway, serine and triacylglycerol biosynthesis, de novo synthesis of nucleotides, amino acids, and lipids 7 .…”

“…Furthermore, recent work reveals that cancer cells are not solely dependent on glycolysis for their energy requirement but also derive energy from mitochondrial respiration [15][16][17] . Invasive migratory ovarian cancer cells and ovarian cancer stem cells have been shown to display metabolic heterogeneity and prefer OXPHOS 6,[18][19][20][21] . The cellular function, fuel type and microenvironment cues, and the interplay between these play a central regulating role in energy metabolism in cancer cells [22][23][24] .…”

Primary Cultures Derived From Bovine Papillomavirus-Infected Lesions As Model To Study Metabolic Deregulation

“…By the contrast, most cancer cells increase the glucose uptake and glycolytic rates even in aerobic conditions, converting the pyruvate to lactate [5,27,30,31]. This metabolic switch, known as "Warburg effect", guarantees the ATP supply to cell proliferation, reducing the ROS levels, which can lead to apoptosis, conferring a protective action to cancer cells [5].…”