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 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 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 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].

scholarly journals The antioxidant mitochondrial protein UCP2 promotes cancer development connecting the Warburg effect and autophagy

2017 ◽  
Vol 1 (1) ◽  
Author(s):  
Marco Cordani ◽  
Giovanna Butera ◽  
Raffaella Pacchiana ◽  
Massimo Donadelli
Keyword(s):  
Warburg Effect ◽  
Mitochondrial Protein ◽  
Cancer Development ◽  
The Warburg Effect

Not available.

scholarly journals Parkin, a p53 target gene, mediates the role of p53 in glucose metabolism and the Warburg effect

2011 ◽  
Vol 108 (39) ◽  
pp. 16259-16264 ◽  
Author(s):  
C. Zhang ◽  
M. Lin ◽  
R. Wu ◽  
X. Wang ◽  
B. Yang ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Warburg Effect ◽  
Target Gene ◽  
P53 Target Gene ◽  
The Warburg Effect

scholarly journals Regulation of Cancer Metabolism by Deubiquitinating Enzymes: The Warburg Effect

2021 ◽  
Vol 22 (12) ◽  
pp. 6173
Author(s):  
So-Hee Kim ◽  
Kwang-Hyun Baek
Keyword(s):  
Cancer Cells ◽  
Warburg Effect ◽  
Cancer Metabolism ◽  
Ubiquitin Proteasome System ◽  
Deubiquitinating Enzymes ◽  
E3 Ligases ◽  
Glycolysis Pathway ◽  
Ubiquitin Proteasome ◽  
Cell Growth And Proliferation ◽  
The Warburg Effect

Cancer is a disorder of cell growth and proliferation, characterized by different metabolic pathways within normal cells. The Warburg effect is a major metabolic process in cancer cells that affects the cellular responses, such as proliferation and apoptosis. Various signaling factors down/upregulate factors of the glycolysis pathway in cancer cells, and these signaling factors are ubiquitinated/deubiquitinated via the ubiquitin–proteasome system (UPS). Depending on the target protein, DUBs act as both an oncoprotein and a tumor suppressor. Since the degradation of tumor suppressors and stabilization of oncoproteins by either negative regulation by E3 ligases or positive regulation of DUBs, respectively, promote tumorigenesis, it is necessary to suppress these DUBs by applying appropriate inhibitors or small molecules. Therefore, we propose that the DUBs and their inhibitors related to the Warburg effect are potential anticancer targets.

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.

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