scholarly journals Beyond the Warburg Effect: Oxidative and Glycolytic Phenotypes Coexist within the Metabolic Heterogeneity of Glioblastoma

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 202
Author(s):  
Tomás Duraj ◽  
Noemí García-Romero ◽  
Josefa Carrión-Navarro ◽  
Rodrigo Madurga ◽  
Ana Ortiz de Mendivil ◽  
...  

Glioblastoma (GBM) is the most aggressive primary brain tumor, with a median survival at diagnosis of 16–20 months. Metabolism represents a new attractive therapeutic target; however, due to high intratumoral heterogeneity, the application of metabolic drugs in GBM is challenging. We characterized the basal bioenergetic metabolism and antiproliferative potential of metformin (MF), dichloroacetate (DCA), sodium oxamate (SOD) and diazo-5-oxo-L-norleucine (DON) in three distinct glioma stem cells (GSCs) (GBM18, GBM27, GBM38), as well as U87MG. GBM27, a highly oxidative cell line, was the most resistant to all treatments, except DON. GBM18 and GBM38, Warburg-like GSCs, were sensitive to MF and DCA, respectively. Resistance to DON was not correlated with basal metabolic phenotypes. In combinatory experiments, radiomimetic bleomycin exhibited therapeutically relevant synergistic effects with MF, DCA and DON in GBM27 and DON in all other cell lines. MF and DCA shifted the metabolism of treated cells towards glycolysis or oxidation, respectively. DON consistently decreased total ATP production. Our study highlights the need for a better characterization of GBM from a metabolic perspective. Metabolic therapy should focus on both glycolytic and oxidative subpopulations of GSCs.

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 850 ◽  
Author(s):  
Koki Ono ◽  
Shota Takigawa ◽  
Katsuya Yamada

Cancerous tumors comprise cells showing metabolic heterogeneity. Among numerous efforts to understand this property, little attention has been paid to the possibility that cancer cells take up and utilize otherwise unusable substrates as fuel. Here we discuss this issue by focusing on l-glucose, the mirror image isomer of naturally occurring d-glucose; l-glucose is an unmetabolizable sugar except in some bacteria. By combining relatively small fluorophores with l-glucose, we generated fluorescence-emitting l-glucose tracers (fLGs). To our surprise, 2-NBDLG, one of these fLGs, which we thought to be merely a control substrate for the fluorescent d-glucose tracer 2-NBDG, was specifically taken up into tumor cell aggregates (spheroids) that exhibited nuclear heterogeneity, a major cytological feature of malignancy in cancer diagnosis. Changes in mitochondrial activity were also associated with the spheroids taking up fLG. To better understand these phenomena, we review here the Warburg effect as well as key studies regarding glucose uptake. We also discuss tumor heterogeneity involving aberrant uptake of glucose and mitochondrial changes based on the data obtained by fLG. We then consider the use of fLGs as novel markers for visualization and characterization of malignant tumor cells.


2015 ◽  
Vol 43 (6) ◽  
pp. 1187-1194 ◽  
Author(s):  
Stefan Schuster ◽  
Daniel Boley ◽  
Philip Möller ◽  
Heiko Stark ◽  
Christoph Kaleta

For producing ATP, tumour cells rely on glycolysis leading to lactate to about the same extent as on respiration. Thus, the ATP synthesis flux from glycolysis is considerably higher than in the corresponding healthy cells. This is known as the Warburg effect (named after German biochemist Otto H. Warburg) and also applies to striated muscle cells, activated lymphocytes, microglia, endothelial cells and several other cell types. For similar phenomena in several yeasts and many bacteria, the terms Crabtree effect and overflow metabolism respectively, are used. The Warburg effect is paradoxical at first sight because the molar ATP yield of glycolysis is much lower than that of respiration. Although a straightforward explanation is that glycolysis allows a higher ATP production rate, the question arises why cells do not re-allocate protein to the high-yield pathway of respiration. Mathematical modelling can help explain this phenomenon. Here, we review several models at various scales proposed in the literature for explaining the Warburg effect. These models support the hypothesis that glycolysis allows for a higher proliferation rate due to increased ATP production and precursor supply rates.


2015 ◽  
Author(s):  
Stefan Schuster ◽  
Daniel Boley ◽  
Philip Möller ◽  
Christoph Kaleta

For producing ATP, tumor cells rely on glycolysis leading to lactate to about the same extent as on respiration. Thus, they use a higher fraction of glycolysis than the corresponding healthy cells. This is known as the Warburg effect (named after German biochemist Otto Warburg) and also applies to striated muscle cells, activated lymphocytes and microglia, endothelial cells and several other cell types. This effect is paradoxical at first sight because the ATP yield of glycolysis is much lower than that of respiration. Although a straightforward explanation is that glycolysis allows a higher ATP production rate, the question arises why the cell does not re-allocate protein to the high-yield pathway of respiration. We tackle this question by a minimal model only including three combined reactions. We consider the case where the cell can allocate protein on several enzymes in a varying distribution and model this by a linear programming problem in which not only the rates but also the maximal velocities are variable. Depending on side conditions and on protein costs, this leads to pure respiration, pure glycolysis, and respirofermentation as a mixed flux distribution.


Theranostics ◽  
2018 ◽  
Vol 8 (17) ◽  
pp. 4765-4780 ◽  
Author(s):  
Christian Hundshammer ◽  
Miriam Braeuer ◽  
Christoph A. Müller ◽  
Adam E. Hansen ◽  
Mathias Schillmaier ◽  
...  

2021 ◽  
Author(s):  
Caroline R. Bartman ◽  
Yihui Shen ◽  
Won Dong Lee ◽  
Tara TeSlaa ◽  
Connor S.R. Jankowski ◽  
...  

SummaryThe tricarboxylic acid (TCA) cycle oxidizes carbon substrates to carbon dioxide, with the resulting high energy electrons fed into the electron transport chain to produce ATP by oxidative phosphorylation. Healthy tissues derive most of their ATP from oxidative metabolism, and the remainder from glycolysis. The corresponding balance in tumors remains unclear. Tumors upregulate aerobic glycolysis (the Warburg effect), yet they also typically require an intact TCA cycle and electron transport chain1–6. Recent studies have measured which nutrients contribute carbon to the tumor TCA metabolites7,8, but not tumor TCA flux: how fast the cycle turns. Here, we develop and validate an in vivo dynamic isotope tracing-mass spectrometry strategy for TCA flux quantitation, which we apply to all major mouse organs and to five tumor models. We show that, compared to the tissue of origin, tumor TCA flux is markedly suppressed. Complementary glycolytic flux measurements confirm tumor glycolysis acceleration, but the majority of tumor ATP is nevertheless made aerobically, and total tumor ATP production is suppressed compared to healthy tissues. In murine pancreatic cancer, this is accommodated by downregulation of the major energy-using pathway in the healthy exocrine pancreas, protein synthesis. Thus, instead of being hypermetabolic as commonly assumed, tumors apparently make ATP at a lower than normal rate. We propose that, as cells de-differentiate into cancer, they eschew ATP-intensive processes characteristic of the host tissue, and that the resulting suppressed ATP demand contributes to the Warburg effect and facilitates cancer growth in the nutrient-poor tumor microenvironment.


2020 ◽  
Author(s):  
Bing Han ◽  
Lu Wang ◽  
Meilin Wei ◽  
Cynthia Rajani ◽  
Runming Wei ◽  
...  

AbstractFructose metabolism is increasingly recognized as a preferred energy source for cancer cell proliferation. However, dietary fructose rarely enters the bloodstream. Therefore, it remains unclear how cancer cells acquire a sufficient amount of fructose to supplement their energy needs. Here we report that the cancer cells can convert glucose into fructose through intra- and extracellular polyol pathways. The fructose metabolism bypasses normal aerobic respiration’s self-control to supply excessive metabolites to glycolysis and causes the Warburg effect. Inhibition of fructose production drastically suppressed glycolysis and ATP production in cancers. Furthermore, we determined that a glucose transporter, SLC2A8/GLUT8, exports intracellular fructose to other cells in the tumor microenvironment. Taken together, our study identified overlooked fructose resources for cancer cells as an essential part of their metabolic reprogramming and caused the Warburg effect.Statement of SignificanceOur findings in this study suggest that the Warburg effect is actually achieved by means of fructose metabolism, instead of glucose metabolism alone. Fructose metabolism results in accelerated glycolysis and an increased amount of ATP and key intermediates for anabolic metabolism.


2020 ◽  
Vol 21 (15) ◽  
pp. 5416 ◽  
Author(s):  
Miyako Kurihara-Shimomura ◽  
Tomonori Sasahira ◽  
Hiroyuki Shimomura ◽  
Tadaaki Kirita

Despite dramatic progress in cancer diagnosis and treatment, the five-year survival rate of oral squamous cell carcinoma (OSCC) is still only about 50%. Thus, the need for elucidating the molecular mechanisms underlying OSCC is urgent. We previously identified the peroxidasin gene (PXDN) as one of several novel genes associated with OSCC. Although the PXDN protein is known to act as a tumor-promoting factor associated with the Warburg effect, its function and role in OSCC are poorly understood. In this study, we investigated the expression, function, and relationship with the Warburg effect of PXDN in OSCC. In immunohistochemical analysis of OSCC specimens, we observed that elevated PXDN expression correlated with lymph node metastasis and a diffuse invasion pattern. High PXDN expression was confirmed as an independent predictor of poor prognosis by multivariate analysis. The PXDN expression level correlated positively with that of pyruvate kinase (PKM2) and heme oxygenase-1 (HMOX1) and with lactate and ATP production. No relationship between PXDN expression and mitochondrial activation was observed, and PXDN expression correlated inversely with reactive oxygen species (ROS) production. These results suggest that PXDN might be a tumor progression factor causing a Warburg-like effect in OSCC.


2006 ◽  
Vol 175 (6) ◽  
pp. 913-923 ◽  
Author(s):  
Hélène Pelicano ◽  
Rui-hua Xu ◽  
Min Du ◽  
Li Feng ◽  
Ryohei Sasaki ◽  
...  

Cancer cells exhibit increased glycolysis for ATP production due, in part, to respiration injury (the Warburg effect). Because ATP generation through glycolysis is less efficient than through mitochondrial respiration, how cancer cells with this metabolic disadvantage can survive the competition with other cells and eventually develop drug resistance is a long-standing paradox. We report that mitochondrial respiration defects lead to activation of the Akt survival pathway through a novel mechanism mediated by NADH. Respiration-deficient cells (ρ-) harboring mitochondrial DNA deletion exhibit dependency on glycolysis, increased NADH, and activation of Akt, leading to drug resistance and survival advantage in hypoxia. Similarly, chemical inhibition of mitochondrial respiration and hypoxia also activates Akt. The increase in NADH caused by respiratory deficiency inactivates PTEN through a redox modification mechanism, leading to Akt activation. These findings provide a novel mechanistic insight into the Warburg effect and explain how metabolic alteration in cancer cells may gain a survival advantage and withstand therapeutic agents.


2020 ◽  
Vol 4 (Supplement_1) ◽  
pp. 741-741
Author(s):  
Raul Mostoslavsky

Abstract In recent years, chromatin regulators have emerged as key modulators in cancer. We discovered that the mammalian histone deacetylase SIRT6 is a key chromatin factor, modulating expression of metabolic, developmental, and ribosomal protein genes. In recent studies, we identified a loss of function mutation in SIRT6 behind a human syndrome of perinatal lethality. In the context of cancer, we found SIRT6 to act as a robust tumor suppressor, by modulating glucose metabolism. As Otto Warburg described decades ago, cancer cells exhibit glycolytic metabolism, where pyruvate, instead of contributing to ATP production in the mitochondria, is converted to lactate even under normoxia conditions. We found SIRT6 as the first chromatin factor in charge of suppressing the Warburg effect in colon and skin cancer. At the cellular level, SIRT6 inactivation leads to increased cellular glucose uptake, higher lactate production and decreased mitochondrial activity. Our results indicate that SIRT6 directly regulates expression of several key glycolytic and ribosomal genes, co-repressing Hif1a and Myc, respectively, and acting as a histone H3 lysine9 (H3K9) and lysine 56 (H3K56) deacetylase. Notably, we recently identified SIRT6 as the first deacetylase to specifically inhibit transcriptional elongation, rather than initiation, in its targets. Strikingly, we determined in new studies that such glycolytic switch provides an advantage even at the early initiating cancer stem cells stage, in what we identified as the cell-of-origin for the Warburg effect. In addition, we found SIRT6 to act as a robust tumor suppressor in the context of pancreatic cancer. However, in this case, SIRT6 did not influence metabolism, but rather silenced expression of the developmental gene Lin28b, in this way protecting against aggressive undifferentiated pancreatic adenocarcinoma. Our studies highlight the important role epigenetic factors, such as SIRT6, play in protecting against tumor progression by providing “epigenetic plasticity”, inhibiting adaptive responses in transformed cells.


2015 ◽  
Author(s):  
Stefan Schuster ◽  
Daniel Boley ◽  
Philip Möller ◽  
Christoph Kaleta

For producing ATP, tumor cells rely on glycolysis leading to lactate to about the same extent as on respiration. Thus, they use a higher fraction of glycolysis than the corresponding healthy cells. This is known as the Warburg effect (named after German biochemist Otto Warburg) and also applies to striated muscle cells, activated lymphocytes and microglia, endothelial cells and several other cell types. This effect is paradoxical at first sight because the ATP yield of glycolysis is much lower than that of respiration. Although a straightforward explanation is that glycolysis allows a higher ATP production rate, the question arises why the cell does not re-allocate protein to the high-yield pathway of respiration. We tackle this question by a minimal model only including three combined reactions. We consider the case where the cell can allocate protein on several enzymes in a varying distribution and model this by a linear programming problem in which not only the rates but also the maximal velocities are variable. Depending on side conditions and on protein costs, this leads to pure respiration, pure glycolysis, and respirofermentation as a mixed flux distribution.


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