Otto Warburg’s contributions to current concepts of cancer metabolism. Nat Rev Cancer
ABSTRACT Otto Warburg pioneered quantitative investigations of cancer cell metabolism, as well as photosynthesis and respiration. Warburg and co-workers showed in the 1920s that, under aerobic conditions, tumour tissues metabolize approximately tenfold more glucose to lactate in a given time than normal tissues, a phenomenon known as the Warburg effect. However, this increase in aerobic glycolysis in cancer cells is often erroneously thought to occur instead of mitochondrial respiration and has been misinterpreted as evidence for damage to respiration instead of damage to the regulation of glycolysis. In fact, many cancers exhibit the Warburg effect while retaining mitochondrial respiration. We re-examine Warburg's observations in relation to the current concepts of cancer metabolism as being intimately linked to alterations of mitochondrial DNA, oncogenes and tumour suppressors, and thus readily exploitable for cancer therapy.
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- "KEY WORDS: ACETYL-CoA; ACETYL COENZYME A; ACETYL-CoA SYNTHETASE; ACETYLATION; DEACETYLATION; FATTY ACID; GLYCERYL TRIACETATE; KETOGENIC DIET; METABOLISM; KETONE BODY; METABOLISM; REVIEW F or a century it has been Q3 debated whether metabolic or genetic alterations were the predominant basis for carcinogenesis since Peyton Rous proposed that caloric restriction could reduce tumor growth and Theodor Boveri suggested that cancer could arise from chromosomal segregation defects during cell division. The metabolic approach to cancer therapy gained support when Otto Warburg noted that blocking both respiration and fermentation killed cancer cells for want of energy and that most cancer cells displayed high rates of glycolysis and lactate production, even in the presence of adequate oxygen (i.e., aerobic glycolysis, Warburg effect) [Koppenol et al., 2011]. Despite Warburg 0 s seminal findings, cancer metabolism research became marginalized by the discoveries of oncogenes and tumor suppressors. "
ABSTRACT: Metabolic networks are significantly altered in neoplastic cells. This altered metabolic program leads to increased glycolysis and lipogenesis and decreased dependence on oxidative phosphorylation and oxygen consumption. Despite their limited mitochondrial respiration, cancer cells, nonetheless, derive sufficient energy from alternative carbon sources and metabolic pathways to maintain cell proliferation. They do so, in part, by utilizing fatty acids, amino acids, ketone bodies and acetate, in addition to glucose. The alternative pathways used in the metabolism of these carbon sources provide opportunities for therapeutic manipulation. Acetate, in particular, has garnered increased attention in the context of cancer as both an epigenetic regulator of posttranslational protein modification, and as a carbon source for cancer cell biomass accumulation. However, to date, the data have not provided a clear understanding of the precise roles that protein acetylation and acetate oxidation play in carcinogenesis, cancer progression or treatment. This review highlights some of the major issues, discrepancies and opportunities associated with the manipulation of acetate metabolism and acetylation-based signaling in cancer development and treatment. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.Journal of Cellular Biochemistry 08/2015; DOI:10.1002/jcb.25305 · 3.37 Impact Factor
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- "While supporting bioenergetics is a critical function of respiration in mammalian cells, many proliferating cells display increased fermentation, which alone can be sufficient to supply ATP (Gottlieb and Tomlinson, 2005). In contrast to most normal tissues, cancer cells consume increased amounts of glucose and metabolize much of this glucose to lactate even in the presence of ample oxygen (Koppenol et al., 2011; Warburg et al., 1924). This phenotype , termed aerobic glycolysis or the Warburg effect, was initially hypothesized to result from diminished mitochondrial function (Warburg, 1956). "
ABSTRACT: Mitochondrial respiration is important for cell proliferation; however, the specific metabolic requirements fulfilled by respiration to support proliferation have not been defined. Here, we show that a major role of respiration in proliferating cells is to provide electron acceptors for aspartate synthesis. This finding is consistent with the observation that cells lacking a functional respiratory chain are auxotrophic for pyruvate, which serves as an exogenous electron acceptor. Further, the pyruvate requirement can be fulfilled with an alternative electron acceptor, alpha-ketobutyrate, which provides cells neither carbon nor ATP. Alpha-ketobutyrate restores proliferation when respiration is inhibited, suggesting that an alternative electron acceptor can substitute for respiration to support proliferation. We find that electron acceptors are limiting for producing aspartate, and supplying aspartate enables proliferation of respiration deficient cells in the absence of exogenous electron acceptors. Together, these data argue a major function of respiration in proliferating cells is to support aspartate synthesis. Copyright © 2015 Elsevier Inc. All rights reserved.Cell 07/2015; 162(3):552-563. DOI:10.1016/j.cell.2015.07.017 · 33.12 Impact Factor
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- "In this initial report, Warburg postulated that cancer cells relied on glycolysis due to defective respiration. Near the end of his career he modified his position, acknowledging that the idea of damaged respiration in cancer cells had led to " fruitless controversy " . Current evidence indeed indicates that mitochondria still function in cancer cells but, in addition they rely on aerobic glycolysis to support the pentose phosphate pathway and glutamine to sustain the TCA cycle Fig. "
ABSTRACT: In the absence of oxygen human life is measured in minutes. In the presence of oxygen, normal metabolism generates reactive species (ROS) that have the potential to cause cell injury contributing to human aging and disease. Between these extremes, organisms have developed means for sensing oxygen and ROS and regulating their cellular processes in response. Redox signaling contributes to the control of cell proliferation and death. Aberrant redox signaling underlies many human diseases. The attributes acquired by altered redox homeostasis in cancer cells illustrate this particularly well. This teaching review and the accompanying illustrations provide an introduction to redox biology and signaling aimed at instructors of graduate and medical students. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.04/2015; 87. DOI:10.1016/j.redox.2015.04.002