Warburg's Observation Research Articles

The Warburg hypothesis and weak ELF biointeractions

ABSTRACTThe Warburg observation concerning ATP generation in cancer cells is analyzed with regard to the likely involvement of H+ resonance effects on the angular velocity of the ATP synthase rotor. It is reasonable to expect that the variety of diseases associated with mitochondrial dysfunction may in part be related to the ATP synthase rate of rotation. Experimental measurements of ATP synthase rotational rates, as found in the literature, are consistent with what might be expected from the ion cyclotron resonance (ICR) frequencies of protons moving under a Lorentz force determined by the approximate surface intensity of the geomagnetic field (~26-65 ?T). One research approach proposes that applying the electronic sum of two critical multiple resonance frequencies simultaneously may serve to more closely resemble real world biochemical changes as compared to applying these frequencies sequentially. Accordingly, it is suggested that applying the sum of the two individual resonance frequencies corresponding to H+ and H3O+ has the capacity to both increase proton density as well as couple to ATP synthase rotation. Not only will this tend to stabilize the F0 rotational rate but also perhaps make it feasible to control this rate, thereby providing a new and potentially efficacious means of treating diseases connected to mitochondrial dysfunction electromagnetically.

A Tumor Agnostic Therapeutic Strategy for Hexokinase 1-Null/Hexokinase 2-Positive Cancers.

Since Warburg's observation that most cancers exhibit elevated glycolysis, decades of research have attempted to reduce tumor glucose utilization as a therapeutic approach. Hexokinase (HK) activity is the first glycolytic enzymatic step; despite many attempts to inhibit HK activity, none has reached clinical application. Identification of HK isoforms, and recognition that most tissues express only HK1 while most tumors express HK1 and HK2, stimulated reducing HK2 activity as a therapeutic option. However, studies using HK2 shRNA and isogenic HK1+HK2- and HK1+HK2+ tumor cell pairs demonstrated that tumors expressing only HK1, while exhibiting reduced glucose consumption, progressed in vivo as well as tumors expressing both HK1 and HK2. However, HK1-HK2+ tumor subpopulations exist among many cancers. shRNA HK2 suppression in HK1-HK2+ liver cancer cells reduced xenograft tumor progression, in contrast to HK1+HK2+ cells. HK2 inhibition, and partial inhibition of both oxidative phosphorylation and fatty acid oxidation using HK2 shRNA and small-molecule drugs, prevented human liver HK1-HK2+ cancer xenograft progression. Using human multiple myeloma xenografts and mouse allogeneic models to identify potential clinical translational agents, triple therapies that include antisense HK2 oligonucleotides, metformin, and perhexiline prevent progression. These results suggest an agnostic approach for HK1-HK2+ cancers, regardless of tissue origin.

P1.03-003 The Warburg Effect: Persistence of Stem Cell Metabolism in Lung Cancer as Failure of Differentiation

Two recent observations are relevant to explaining Warburg's observation the cancers constitutively utilize glycolysis in the presence of oxygen sufficient for oxidative phosphorylation. First, the metabolism of stem cells has been shown to be constitutive (‘aerobic’) glycolysis, with differentiation involving a transition to oxidative phosphorylation. Second, the degree of glucose uptake by a cancer has been associated with histologic differentiation. We hypothesized that the high levels of glucose uptake observed in poorly differentiated lung cancers may reflect persistence in cancers of the glycolytic metabolism of stem cells that fail to fully differentiate. Tumor glucose uptake was measured by FDG-PET in 859 patients with histologically diverse cancers including NSCLC. We used normal mixture modeling to explore SUV distributions and tested for association between glucose uptake and histological differentiation, risk of lymph node metastasis, and survival. Using microarray data, we performed pathway and transcription factor analyses to compare tumors with high/low glucose uptake. Well-differentiated NSCLC had low FDG uptake, and moderately/poorly differentiated tumors higher uptake. The distribution of FDG-PET uptake was modal with a low peak at SUV 2-4 and a high peak at SUV 8-11. The cancers in the two peaks were clinically distinct in terms of the risk of nodal metastases and of death. Carbohydrate metabolism-related and pentose/nucleotide synthesis-related genes were elevated in the high SUV clusters, Krebs cycle/glutamine metabolism-related genes were elevated in the low SUV mode samples. Expression of Myc target genes was associated with SUV mode, but Nanog, Sox2, Oct4 and PRC2 where not. The biological basis for the Warburg effect is persistence of stem cell metabolism in lung cancers as a failure to transition from glycolysis-utilizing undifferentiated cells to oxidative phosphorylation-utilizing differentiated cells. Lung cancers cluster along the differentiation pathway into two groups. Our results have implications for determining prognosis, cancer screening and surveillance after resection.

Chicken or the egg: Warburg effect and mitochondrial dysfunction.

Compared with normal cells, cancer cells show alterations in many cellular processes, including energy metabolism. Studies on cancer metabolism started with Otto Warburg's observation at the beginning of the last century. According to Warburg, cancer cells rely on glycolysis more than mitochondrial respiration for energy production. Considering that glycolysis yields much less energy compared with mitochondrial respiration, Warburg hypothesized that mitochondria must be dysfunctional and this is the initiating factor for cancer formation. However, this hypothesis did not convince every scientist in the field. Some believed the opposite: the reduction in mitochondrial activity is a result of increased glycolysis. This discrepancy of opinions is ongoing. In this review, we will discuss the alterations in glycolysis, pyruvate metabolism, and the Krebs cycle in cancer cells and focus on cause and consequence.

Lactate as an insidious metabolite due to the Warburg effect.

Although oncogenetics remains a critical component of cancer biology and therapeutic research, recent interest has been taken towards the non-genetic features of tumour development and progression, such as cancer metabolism. Specifically, it has been observed that tumour cells are inclined to preferentially undergo glycolysis despite presence of adequate oxygen. First reported by Otto Warburg in the 1920s, and now termed the 'Warburg effect', this aberrant metabolism has become of particular interest due to the prevalence of the fermentation phenotype in a variety of cancers studied. Consequently, this phenotype has proven to play a pivotal role in cancer proliferation. As such Warburg's observations are now being integrated within the modern paradigms of cancer and in this review we explore the role of lactate as an insidious metabolite due to the Warburg effect.

Hypoxia and oxygenation induce a metabolic switch between pentose phosphate pathway and glycolysis in glioma stem-like cells

Fluctuations in oxygen tension during tissue remodeling impose a major metabolic challenge in human tumors. Stem-like tumor cells in glioblastoma, the most common malignant brain tumor, possess extraordinary metabolic flexibility, enabling them to initiate growth even under non-permissive conditions. We identified a reciprocal metabolic switch between the pentose phosphate pathway (PPP) and glycolysis in glioblastoma stem-like (GS) cells. Expression of PPP enzymes is upregulated by acute oxygenation but downregulated by hypoxia, whereas glycolysis enzymes, particularly those of the preparatory phase, are regulated inversely. Glucose flux through the PPP is reduced under hypoxia in favor of flux through glycolysis. PPP enzyme expression is elevated in human glioblastomas compared to normal brain, especially in highly proliferative tumor regions, whereas expression of parallel preparatory phase glycolysis enzymes is reduced in glioblastomas, except for strong upregulation in severely hypoxic regions. Hypoxia stimulates GS cell migration but reduces proliferation, whereas oxygenation has opposite effects, linking the metabolic switch to the "go or grow" potential of the cells. Our findings extend Warburg's observation that tumor cells predominantly utilize glycolysis for energy production, by suggesting that PPP activity is elevated in rapidly proliferating tumor cells but suppressed by acute severe hypoxic stress, favoring glycolysis and migration to protect cells against hypoxic cell damage.

Abstract LB-86: Metabolic presentation of bladder cancer in urine

Abstract Introduction and Objective Recently it has been shown that many oncogenes regulate metabolism, revitalizing interest in Warburg's observation of aerobic glycolysis by tumors. We and others have demonstrated the utility of metabolic signatures for the diagnosis of cancer in minimally invasive clinical samples and the differential diagnosis of cancer by stage and grade using biopsy samples. Here we apply state of the art metabolomic analysis to the diagnosis of bladder cancer from urine samples. Methods A case controlled study of ten transitional cell carcinoma (TCC) patients and matched non-TCC controls was performed. Briefly, clarified urine was extracted into aqueous methanol and characterized using three analytical platforms (gas chromatography mass spectrometry (MS) and ultrahigh performance liquid chromatography tandem MS). Spectral data were compared against an in-house library of over 2500 authentic standards and the relative abundance of each compound within the data set was calculated. Two-group statistics (R) and multivariate analysis (Array Studio, OmicSoft) were performed to identify differentially abundant metabolites. Results Three hundred and sixty-seven compounds were identified in this study and polypharmacy did not compromise the quality of the signal obtained for endogenous metabolites. Thirteen compounds, arising from diverse metabolic pathways, including: energetics, oxidative stress and amino acid catabolism, exhibited statistically significant differences between TCC and non-TCC cases. Principal component (PC) analysis demonstrated that the majority of the information in these metabolites (PC 1) separated TCC from non-TCC cases. Conclusions These data indicate the feasibility of a novel, non-invasive, urine-based diagnostic test to detect the presence of bladder tumors. Such a test could be positioned for use in conjunction with the current standard of care to improve patient management. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-86. doi:1538-7445.AM2012-LB-86

Aerobic Glycolysis: Meeting the Metabolic Requirements of Cell Proliferation

Warburg's observation that cancer cells exhibit a high rate of glycolysis even in the presence of oxygen (aerobic glycolysis) sparked debate over the role of glycolysis in normal and cancer cells. Although it has been established that defects in mitochondrial respiration are not the cause of cancer or aerobic glycolysis, the advantages of enhanced glycolysis in cancer remain controversial. Many cells ranging from microbes to lymphocytes use aerobic glycolysis during rapid proliferation, which suggests it may play a fundamental role in supporting cell growth. Here, we review how glycolysis contributes to the metabolic processes of dividing cells. We provide a detailed accounting of the biosynthetic requirements to construct a new cell and illustrate the importance of glycolysis in providing carbons to generate biomass. We argue that the major function of aerobic glycolysis is to maintain high levels of glycolytic intermediates to support anabolic reactions in cells, thus providing an explanation for why increased glucose metabolism is selected for in proliferating cells throughout nature.

Otto Warburg's contributions to current concepts of cancer metabolism

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.

Oxygen Consumption Can Regulate the Growth of Tumors, a New Perspective on the Warburg Effect

BackgroundThe unique metabolism of tumors was described many years ago by Otto Warburg, who identified tumor cells with increased glycolysis and decreased mitochondrial activity. However, “aerobic glycolysis” generates fewer ATP per glucose molecule than mitochondrial oxidative phosphorylation, so in terms of energy production, it is unclear how increasing a less efficient process provides tumors with a growth advantage.Methods/FindingsWe carried out a screen for loss of genetic elements in pancreatic tumor cells that accelerated their growth as tumors, and identified mitochondrial ribosomal protein L28 (MRPL28). Knockdown of MRPL28 in these cells decreased mitochondrial activity, and increased glycolysis, but paradoxically, decreased cellular growth in vitro. Following Warburg's observations, this mutation causes decreased mitochondrial function, compensatory increase in glycolysis and accelerated growth in vivo. Likewise, knockdown of either mitochondrial ribosomal protein L12 (MRPL12) or cytochrome oxidase had a similar effect. Conversely, expression of the mitochondrial uncoupling protein 1 (UCP1) increased oxygen consumption and decreased tumor growth. Finally, treatment of tumor bearing animals with dichloroacetate (DCA) increased pyruvate consumption in the mitochondria, increased total oxygen consumption, increased tumor hypoxia and slowed tumor growth.ConclusionsWe interpret these findings to show that non-oncogenic genetic changes that alter mitochondrial metabolism can regulate tumor growth through modulation of the consumption of oxygen, which appears to be a rate limiting substrate for tumor proliferation.

Mitochondrial Uncoupling and the Warburg Effect: Molecular Basis for the Reprogramming of Cancer Cell Metabolism

The precise mitochondrial alterations that underlie the increased dependence of cancer cells on aerobic glycolysis for energy generation have remained a mystery. Recent evidence suggests that mitochondrial uncoupling-the abrogation of ATP synthesis in response to mitochondrial membrane potential-promotes the Warburg effect in leukemia cells, and may contribute to chemoresistance. Intriguingly, leukemia cells cultured on bone marrow-derived stromal feeder layers are more resistant to chemotherapy, increase the expression of uncoupling protein 2, and decrease the entry of pyruvate into the Krebs cycle-without compromising the consumption of oxygen, suggesting a shift to the oxidation of nonglucose carbon sources to maintain mitochondrial integrity and function. Because fatty acid oxidation has been linked to chemoresistance and mitochondrial uncoupling, it is tempting to speculate that Warburg's observations may indeed be the result of the preferential oxidation of fatty acids by cancer cell mitochondria. Therefore, targeting fatty acid oxidation or anaplerotic pathways that support fatty acid oxidation may provide additional therapeutic tools for the treatment of hematopoietic malignancies.

A history of research on yeasts 9: regulation of sugar metabolism1

A history of research on yeasts 9: regulation of sugar metabolism1

Kinetics of Photosynthesis

BALY and Morgan1 have proposed kinetic equations which account for observations of Warburg2 and Emerson3 on the rate of photosynthesis. We wish to direct attention to one of Warburg's observations which is not in accordance with their equations. At low light intensities, the temperature coefficient of photosynthesis approaches unity, while at low carbon dioxide concentrations it remains high. We have confirmed this for five different species of algae. This leads us to suppose that carbon dioxide is a reactant in the temperature-sensitive reaction, rather than in the photochemical reaction, where Baly and Morgan placed it. Their assumption seems to us untenable because it leads to equations in which light intensity and carbon dioxide concentration are interchangeable, and because according to photo chemical principles a photochemical primary process is unimolecular, taking place immediately on the absorption of light.

METHYLENE BLUE: A SYNERGIST, NOT AN ANTIDOTE, FOR CARBON MONOXIDE

Methylene blue (methylthionine chloride U. S. P.) has recently been much in the lay press, not only as an antidote for cyanide, which it is, but also for carbon monoxide, which it is not. P. J. Hanzlik 1 has reviewed the evidence that this substance is an antidote to cyanide. As he points out, the antagonistic property of methylene blue for cyanide was demonstrated experimentally as early as 1926 and has been confirmed by more recent work. On the other hand, the alleged antagonism between methylene blue and carbon monoxide has no valid support. The theoretical basis of the claim for an antidotal action is derived from the brilliant investigations of Warburg; 2 but Warburg's observations on isolated tissues have no real bearing on carbon monoxide asphyxia in man. The experiments of Matilda M. Brooks 3 on animals are of little evidential value. The fact is that in its effect