scholarly journals Making ATP fast and slow: do yeasts play a mixed strategy to metabolise glucose?

2019 ◽  
Author(s):  
Hadiseh Safdari ◽  
Mehdi Sadeghi ◽  
Ata Kalirad
Keyword(s):  
Glucose Metabolism ◽  
Warburg Effect ◽  
Mixed Strategy ◽  
Crabtree Effect ◽  
Metabolic Switch ◽  
Theoretical Approaches ◽  
Common Resource ◽  
Game Theoretical Approach ◽  
The Individual ◽  
The Warburg Effect

AbstractThe ability of some microorganisms to switch from respiration to fermentation in the presence of oxygen-the so-called Crabtree effect-has been a fascinating subject of study at the theoretical and experimental fronts. Game-theoretical approaches have been routinely used to examine and explain the way a microorganism, such as yeast, would switch between the two ATP-producing pathways, i.e., respiration and fermentation. Here we attempt to explain the switch between respiration and fermentation in yeast by constructing a simple metabolic switch. We then utilise an individual-based model, in which each individual is equipped with all the relevant chemical reactions, to see how cells equipped with such metabolic switch would behave in different conditions. We further investigate our proposed metabolic switch using the game-theoretical approach. Based on this model, we postulate that individuals play a mixed game of glucose metabolism in the population. This approach not only sheds some light in the varieties of metabolic regulations that can be utilised by the individual in the population in competition with others for a common resource, it would also allow a better understanding of the causes of the Warburg effect and similar phenomena observed in nature.

scholarly journals Influence of SNF1 complex on growth, glucose metabolism and mitochondrial respiration ofSaccharomyces cerevisiae

2018 ◽  
Author(s):  
Cecilia Martinez-Ortiz ◽  
Andres Carrillo-Garmendia ◽  
Blanca Flor Correa-Romero ◽  
Melina Canizal-García ◽  
Juan Carlos González-Hernández ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Mitochondrial Respiration ◽  
Warburg Effect ◽  
Gene Deletion ◽  
Glycolytic Flux ◽  
Crabtree Effect ◽  
Main Pathway ◽  
Molecular Etiology ◽  
The Warburg Effect

AbstractThe switch of mitochondrial respiration to fermentation as the main pathway to produce ATP through the increase of glycolytic flux is known as the Crabtree effect. The elucidation of the molecular mechanism of the Crabtree effect may have important applications in ethanol production and lay the groundwork for the Warburg effect, which is essential in the molecular etiology of cancer. A key piece in this mechanism could be Snf1p, which is a protein that participates in the nutritional response that includes glucose metabolism. Thus, this work aimed to recognize the role of the SNF1 complex on the glycolytic flux and mitochondrial respiration, to gain insights about its relationship with the Crabtree effect. Herein, we found that inSaccharomyces cerevisiaecells grown at 1% glucose, mutation ofSNF1gene decreased glycolytic flux, increased NAD(P)H, enhancedHXK2gene transcription, and decreased mitochondrial respiration. Meanwhile, the same mutation increased the mitochondrial respiration of cells grown at 10% glucose. Moreover,SNF4gene deletion increased respiration and growth at 1% of glucose. In the case of theGAL83gene, we did not detect any change in mitochondrial respiration or growth. Altogether, these findings indicate thatSNF1is vital to switch from mitochondrial respiration to fermentation.

scholarly journals Hyperbaric Oxygen Therapy Represses the Warburg Effect and Epithelial–Mesenchymal Transition in Hypoxic NSCLC Cells via the HIF-1α/PFKP Axis

2021 ◽  
Vol 11 ◽  
Author(s):  
Linling Zhang ◽  
Jingjing Ke ◽  
Shengping Min ◽  
Nan Wu ◽  
Fei Liu ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Cell Lines ◽  
Hyperbaric Oxygen ◽  
Hyperbaric Oxygen Therapy ◽  
Warburg Effect ◽  
Oxygen Therapy ◽  
Nsclc Cell ◽  
Glycolytic Flux ◽  
Mesenchymal Transition ◽  
The Warburg Effect

BackgroundTumor cells initiate hypoxia-induced mechanisms to fuel cell proliferation, invasion, and metastasis, largely mediated by low O2-responsive Hypoxia-Inducible Factor 1 Alpha (HIF-1α). Therefore, hyperbaric oxygen therapy (HBO) is now being studied in cancer patients, but its impact upon non-small-cell lung cancer (NSCLC) cell metabolism remains uncharacterized.MethodsWe employed the NSCLC cell lines A549 and H1299 for in vitro studies. Glucose uptake, pyruvate, lactate, and adenosine triphosphate (ATP) assays were used to assess aerobic glycolysis (Warburg effect). A quantitative glycolytic flux model was used to analyze the flux contributions of HIF-1α-induced glucose metabolism genes. We used a Lewis lung carcinoma (LLC) murine model to measure lung tumorigenesis in C57BL/6J mice.ResultsHBO suppressed hypoxia-induced HIF-1α expression and downstream HIF-1α signaling in NSCLC cells. One HIF-1α-induced glucose metabolism gene—Phosphofructokinase, Platelet (PFKP)—most profoundly enhanced glycolytic flux under both low- and high-glucose conditions. HBO suppressed hypoxia-induced PFKP transactivation and gene expression via HIF-1α downregulation. HBO’s suppression of the Warburg effect, suppression of hyperproliferation, and suppression of epithelial-to-mesenchymal transition (EMT) in hypoxic NSCLC cell lines is mediated by the HIF-1α/PFKP axis. In vivo, HBO therapy inhibited murine LLC lung tumor growth in a Pfkp-dependent manner.ConclusionsHBO’s repression of the Warburg effect, repression of hyperproliferation, and repression of EMT in hypoxic NSCLC cells is dependent upon HIF-1α downregulation. HIF-1α’s target gene PFKP functions as a central mediator of HBO’s effects in hypoxic NSCLC cells and may represent a metabolic vulnerability in NSCLC tumors.

scholarly journals III. Cellular ultrastructures in situ as key to understanding tumor energy metabolism: biological significance of the Warburg effect

F1000Research ◽  
2013 ◽  
Vol 2 ◽  
pp. 10 ◽  
Author(s):  
Halina Witkiewicz ◽  
Phil Oh ◽  
Jan E Schnitzer
Keyword(s):  
Warburg Effect ◽  
Cancer Metabolism ◽  
Biological Significance ◽  
Tissue Growth ◽  
High Rate ◽  
Intermediate Form ◽  
Malignant Cells ◽  
Metabolic Switch ◽  
The Warburg Effect

Despite the universality of metabolic pathways, malignant cells were found to have their metabolism reprogrammed to generate energy by glycolysis even under normal oxygen concentrations (the Warburg effect). Therefore, the pathway energetically 18 times less efficient than oxidative phosphorylation was implicated to match increased energy requirements of growing tumors. The paradox was explained by an abnormally high rate of glucose uptake, assuming unlimited availability of substrates for tumor growth in vivo. However, ultrastructural analysis of tumor vasculature morphogenesis showed that the growing tissue regions did not have continuous blood supply and intermittently depended on autophagy for survival. Erythrogenic autophagy, and resulting ATP generation by glycolysis, appeared critical to initiating vasculature formation where it was missing. This study focused on ultrastructural features that reflected metabolic switch from aerobic to anaerobic. Morphological differences between and within different types of cells were evident in tissue sections. In cells undergoing nucleo-cytoplasmic conversion into erythrosomes (erythrogenesis), gradual changes led to replacing mitochondria with peroxisomes, through an intermediate form connected to endoplasmic reticulum. Those findings related to the issue of peroxisome biogenesis and to the phenomenon of hemogenic endothelium. Mitochondria were compacted also during mitosis. In vivo, cells that lost and others that retained capability to use oxygen coexisted side-by-side; both types were important for vasculature morphogenesis and tissue growth. Once passable, the new vasculature segment could deliver external oxygen and nutrients. Nutritional and redox status of microenvironment had similar effect on metabolism of malignant and non-malignant cells demonstrating the necessity to maintain structure-energy equivalence in all living cells. The role of glycolysis in initiating vasculature formation, and in progression of cell cycle through mitosis, indicated that Warburg effect had a fundamental biological significance extending to non-malignant tissues. The approach used here could facilitate integration of accumulated cyber knowledge on cancer metabolism into predictive science.

scholarly journals Dysfunction of an energy sensor NFE2L1 triggers uncontrollable AMPK signal and glucose metabolism reprogramming

2021 ◽  
Author(s):  
Qiufang Yang ◽  
Wenshan Zhao ◽  
Yadi Xing ◽  
Peng Li ◽  
Xiaowen Zhou ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Warburg Effect ◽  
Metabolic Diseases ◽  
Energy State ◽  
Glucose Deprivation ◽  
Cancer Development ◽  
Energy Sensor ◽  
Dual Sensor ◽  
Glycolysis Pathway ◽  
The Warburg Effect

AbstractNFE2L1 (also called Nrf1) acts a core regulator of redox signaling and metabolism homeostasis, and thus its dysfunction results in multiple systemic metabolic diseases. However, the molecular mechanism(s) by which NFE2L1 regulates glycose and lipid metabolism is still elusive. Here, we found that the loss of NFE2L1 in human HepG2 cells led to a lethal phenotype upon glucose deprivation. The uptake of glucose was also affected by NFE2L1 deficiency. Further experiments unveiled that although the glycosylation of NFE2L1 was monitored through the glycolysis pathway, it enabled to sense the energy state and directly interacted with AMPK. These indicate that NFE2L1 can serve as a dual sensor and regulator of glucose homeostasis. In-depth sights into transcriptome, metabolome and seahorse data further unraveled that glucose metabolism was reprogrammed by disruption of NFE2L1, so as to aggravate the Warburg effect in NFE2L1-silenced hepatoma cells, along with the mitochondrial damage observed under the electron microscope. Collectively, these demonstrate that disfunction of NFE2L1 triggers the uncontrollable signaling by AMPK towards glucose metabolism reprogramming in the liver cancer development.

scholarly journals Insulin-Like Growth Factor 1 (IGF-1) Signaling in Glucose Metabolism in Colorectal Cancer

2021 ◽  
Vol 22 (12) ◽  
pp. 6434
Author(s):  
Aldona Kasprzak
Keyword(s):  
Colorectal Cancer ◽  
Growth Factor ◽  
Glucose Metabolism ◽  
Warburg Effect ◽  
Mapk Signaling ◽  
Colorectal Carcinogenesis ◽  
Insulin Like Growth Factor ◽  
Aberrant Expression ◽  
The Warburg Effect

Colorectal cancer (CRC) is one of the most common aggressive carcinoma types worldwide, characterized by unfavorable curative effect and poor prognosis. Epidemiological data re-vealed that CRC risk is increased in patients with metabolic syndrome (MetS) and its serum components (e.g., hyperglycemia). High glycemic index diets, which chronically raise post-prandial blood glucose, may at least in part increase colon cancer risk via the insulin/insulin-like growth factor 1 (IGF-1) signaling pathway. However, the underlying mechanisms linking IGF-1 and MetS are still poorly understood. Hyperactivated glucose uptake and aerobic glycolysis (the Warburg effect) are considered as a one of six hallmarks of cancer, including CRC. However, the role of insulin/IGF-1 signaling during the acquisition of the Warburg metabolic phenotypes by CRC cells is still poorly understood. It most likely results from the interaction of multiple processes, directly or indirectly regulated by IGF-1, such as activation of PI3K/Akt/mTORC, and Raf/MAPK signaling pathways, activation of glucose transporters (e.g., GLUT1), activation of key glycolytic enzymes (e.g., LDHA, LDH5, HK II, and PFKFB3), aberrant expression of the oncogenes (e.g., MYC, and KRAS) and/or overexpression of signaling proteins (e.g., HIF-1, TGF-β1, PI3K, ERK, Akt, and mTOR). This review describes the role of IGF-1 in glucose metabolism in physiology and colorectal carcinogenesis, including the role of the insulin/IGF system in the Warburg effect. Furthermore, current therapeutic strategies aimed at repairing impaired glucose metabolism in CRC are indicated.

scholarly journals Lysine 53 Acetylation of Cytochrome c in Prostate Cancer: Warburg Metabolism and Evasion of Apoptosis

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 802
Author(s):  
Viktoriia Bazylianska ◽  
Hasini A. Kalpage ◽  
Junmei Wan ◽  
Asmita Vaishnav ◽  
Gargi Mahapatra ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cytochrome C ◽  
Warburg Effect ◽  
Structural Features ◽  
Intrinsic Apoptosis ◽  
Metabolic Switch ◽  
Cancer Hallmarks ◽  
Dynamics Simulations ◽  
The Warburg Effect

Prostate cancer is the second leading cause of cancer-related death in men. Two classic cancer hallmarks are a metabolic switch from oxidative phosphorylation (OxPhos) to glycolysis, known as the Warburg effect, and resistance to cell death. Cytochrome c (Cytc) is at the intersection of both pathways, as it is essential for electron transport in mitochondrial respiration and a trigger of intrinsic apoptosis when released from the mitochondria. However, its functional role in cancer has never been studied. Our data show that Cytc is acetylated on lysine 53 in both androgen hormone-resistant and -sensitive human prostate cancer xenografts. To characterize the functional effects of K53 modification in vitro, K53 was mutated to acetylmimetic glutamine (K53Q), and to arginine (K53R) and isoleucine (K53I) as controls. Cytochrome c oxidase (COX) activity analyzed with purified Cytc variants showed reduced oxygen consumption with acetylmimetic Cytc compared to the non-acetylated Cytc (WT), supporting the Warburg effect. In contrast to WT, K53Q Cytc had significantly lower caspase-3 activity, suggesting that modification of Cytc K53 helps cancer cells evade apoptosis. Cardiolipin peroxidase activity, which is another proapoptotic function of the protein, was lower in acetylmimetic Cytc. Acetylmimetic Cytc also had a higher capacity to scavenge reactive oxygen species (ROS), another pro-survival feature. We discuss our experimental results in light of structural features of K53Q Cytc, which we crystallized at a resolution of 1.31 Å, together with molecular dynamics simulations. In conclusion, we propose that K53 acetylation of Cytc affects two hallmarks of cancer by regulating respiration and apoptosis in prostate cancer xenografts.

scholarly journals Everolimus regulates the activity of gemcitabine-resistant pancreatic cancer cells by targeting the Warburg effect via PI3K/AKT/mTOR signaling

2021 ◽  
Vol 27 (1) ◽  
Author(s):  
Jing Cui ◽  
Yao Guo ◽  
Heshui Wu ◽  
Jiongxin Xiong ◽  
Tao Peng
Keyword(s):  
Pancreatic Cancer ◽  
Glucose Metabolism ◽  
Cell Viability ◽  
Cancer Cells ◽  
Warburg Effect ◽  
Aerobic Glycolysis ◽  
Mtor Signaling ◽  
Glucose Transporter 1 ◽  
Pancreatic Cancer Cells ◽  
The Warburg Effect

Abstract Background Gemcitabine (GEM) resistance remains a significant clinical challenge in pancreatic cancer treatment. Here, we investigated the therapeutic utility of everolimus (Evr), an inhibitor of mammalian target of rapamycin (mTOR), in targeting the Warburg effect to overcome GEM resistance in pancreatic cancer. Methods The effect of Evr and/or mTOR overexpression or GEM on cell viability, migration, apoptosis, and glucose metabolism (Warburg effect) was evaluated in GEM-sensitive (GEMsen) and GEM-resistant (GEMres) pancreatic cancer cells. Results We demonstrated that the upregulation of mTOR enhanced cell viability and favored the Warburg effect in pancreatic cancer cells via the regulation of PI3K/AKT/mTOR signaling. However, this effect was counteracted by Evr, which inhibited aerobic glycolysis by reducing the levels of glucose, lactic acid, and adenosine triphosphate and suppressing the expression of glucose transporter 1, lactate dehydrogenase-B, hexokinase 2, and pyruvate kinase M2 in GEMsen and GEMres cells. Evr also promoted apoptosis by upregulating the pro-apoptotic proteins Bax and cytochrome-c and downregulating the anti-apoptotic protein Bcl-2. GEM was minimally effective in suppressing GEMres cell activity, but the therapeutic effectiveness of Evr against pancreatic cancer growth was greater in GEMres cells than that in GEMsen cells. In vivo studies confirmed that while GEM failed to inhibit the progression of GEMres tumors, Evr significantly decreased the volume of GEMres tumors while suppressing tumor cell proliferation and enhancing tumor apoptosis in the presence of GEM. Conclusions Evr treatment may be a promising strategy to target the growth and activity of GEM-resistant pancreatic cancer cells by regulating glucose metabolism via inactivation of PI3K/AKT/mTOR signaling.

scholarly journals Targeting Glucose Metabolism of Cancer Cells with Dichloroacetate to Radiosensitize High-Grade Gliomas

2021 ◽  
Vol 22 (14) ◽  
pp. 7265
Author(s):  
Kristina M. Cook ◽  
Han Shen ◽  
Kelly J. McKelvey ◽  
Harriet E. Gee ◽  
Eric Hau
Keyword(s):  
Glucose Metabolism ◽  
Warburg Effect ◽  
High Grade Glioma ◽  
Glycolytic Flux ◽  
High Grade ◽  
Dna Breaks ◽  
Novel Approach ◽  
Altered Glucose ◽  
Altered Metabolism ◽  
The Warburg Effect

As the cornerstone of high-grade glioma (HGG) treatment, radiotherapy temporarily controls tumor cells via inducing oxidative stress and subsequent DNA breaks. However, almost all HGGs recur within months. Therefore, it is important to understand the underlying mechanisms of radioresistance, so that novel strategies can be developed to improve the effectiveness of radiotherapy. While currently poorly understood, radioresistance appears to be predominantly driven by altered metabolism and hypoxia. Glucose is a central macronutrient, and its metabolism is rewired in HGG cells, increasing glycolytic flux to produce energy and essential metabolic intermediates, known as the Warburg effect. This altered metabolism in HGG cells not only supports cell proliferation and invasiveness, but it also contributes significantly to radioresistance. Several metabolic drugs have been used as a novel approach to improve the radiosensitivity of HGGs, including dichloroacetate (DCA), a small molecule used to treat children with congenital mitochondrial disorders. DCA reverses the Warburg effect by inhibiting pyruvate dehydrogenase kinases, which subsequently activates mitochondrial oxidative phosphorylation at the expense of glycolysis. This effect is thought to block the growth advantage of HGGs and improve the radiosensitivity of HGG cells. This review highlights the main features of altered glucose metabolism in HGG cells as a contributor to radioresistance and describes the mechanism of action of DCA. Furthermore, we will summarize recent advances in DCA’s pre-clinical and clinical studies as a radiosensitizer and address how these scientific findings can be translated into clinical practice to improve the management of HGG patients.

scholarly journals Evolved resistance to GAPDH inhibition results in loss of the Warburg Effect but retains a different state of glycolysis

2019 ◽  
Author(s):  
Maria V. Liberti ◽  
Annamarie E. Allen ◽  
Vijyendra Ramesh ◽  
Ziwei Dai ◽  
Katherine R. Singleton ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Warburg Effect ◽  
Acid Metabolism ◽  
Aerobic Glycolysis ◽  
Specific Inhibitor ◽  
Central Carbon Metabolism ◽  
Glycolytic Enzyme ◽  
Altered State ◽  
The Warburg Effect

SUMMARYAerobic glycolysis or the Warburg Effect (WE) is characterized by increased glucose uptake and incomplete oxidation to lactate. Although ubiquitous, the biological role of the WE remains controversial and whether glucose metabolism is functionally different during fully oxidative glycolysis or during the WE is unknown. To investigate this question, we evolved resistance to koningic acid (KA), a natural product shown to be a specific inhibitor of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a rate-controlling glycolytic enzyme during the WE. We find that KA-resistant cells lose the WE but conduct glycolysis and surprisingly remain dependent on glucose and central carbon metabolism. Consequentially this altered state of glycolysis leads to differential metabolic activity and requirements including emergent activities in and dependencies on fatty acid metabolism. Together, these findings reveal that, contrary to some recent reports, aerobic glycolysis is a functionally distinct entity from conventional glucose metabolism and leads to distinct metabolic requirements and biological functions.

scholarly journals Glucose Metabolism in Cancer: The Warburg Effect and Beyond

2021 ◽  
pp. 3-15 ◽  
Author(s):  
Sminu Bose ◽  
Cissy Zhang ◽  
Anne Le
Keyword(s):  
Glucose Metabolism ◽  
Molecular Biology ◽  
Warburg Effect ◽  
Scientific Community ◽  
Cancer Metabolism ◽  
Cancer Therapies ◽  
Otto Warburg ◽  
New Cancer Therapies ◽  
Open The Doors ◽  
The Warburg Effect

AbstractOtto Warburg observed a peculiar phenomenon in 1924, unknowingly laying the foundation for the field of cancer metabolism. While his contemporaries hypothesized that tumor cells derived the energy required for uncontrolled replication from proteolysis and lipolysis, Warburg instead found them to rapidly consume glucose, converting it to lactate even in the presence of oxygen. The significance of this finding, later termed the Warburg effect, went unnoticed by the broader scientific community at that time. The field of cancer metabolism lay dormant for almost a century awaiting advances in molecular biology and genetics, which would later open the doors to new cancer therapies [2, 3].

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