scholarly journals MPI depletion enhances O-GlcNAcylation of p53 and suppresses the Warburg effect

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Nataly Shtraizent ◽  
Charles DeRossi ◽  
Shikha Nayar ◽  
Ravi Sachidanandam ◽  
Liora S Katz ◽  
...  
Keyword(s):  
Warburg Effect ◽  
Mammalian Cells ◽  
Biosynthetic Pathway ◽  
Cellular Proliferation ◽  
Metabolic Enzyme ◽  
Chemical Methods ◽  
Hexosamine Biosynthetic Pathway ◽  
Glycolytic Intermediate ◽  
Functional Consequences ◽  
The Warburg Effect

Rapid cellular proliferation in early development and cancer depends on glucose metabolism to fuel macromolecule biosynthesis. Metabolic enzymes are presumed regulators of this glycolysis-driven metabolic program, known as the Warburg effect; however, few have been identified. We uncover a previously unappreciated role for Mannose phosphate isomerase (MPI) as a metabolic enzyme required to maintain Warburg metabolism in zebrafish embryos and in both primary and malignant mammalian cells. The functional consequences of MPI loss are striking: glycolysis is blocked and cells die. These phenotypes are caused by induction of p53 and accumulation of the glycolytic intermediate fructose 6-phosphate, leading to engagement of the hexosamine biosynthetic pathway (HBP), increased O-GlcNAcylation, and p53 stabilization. Inhibiting the HBP through genetic and chemical methods reverses p53 stabilization and rescues the Mpi-deficient phenotype. This work provides mechanistic evidence by which MPI loss induces p53, and identifies MPI as a novel regulator of p53 and Warburg metabolism.

scholarly journals MYC regulates metabolism through vesicular transfer of glycolytic kinases

Open Biology ◽  
2021 ◽  
Vol 11 (12) ◽  
Author(s):  
Alexia Tsakaneli ◽  
Victor Corasolla Carregari ◽  
Martina Morini ◽  
Alessandra Eva ◽  
Giuliana Cangemi ◽  
...  
Keyword(s):  
Warburg Effect ◽  
Neuroblastoma Cells ◽  
Mass Spectrometry Analysis ◽  
Target Cells ◽  
Hexokinase Ii ◽  
Childhood Malignancy ◽  
Spectrometry Analysis ◽  
Functional Consequences ◽  
The Warburg Effect

Amplification of the proto-oncogene MYCN is a key molecular aberration in high-risk neuroblastoma and predictive of poor outcome in this childhood malignancy. We investigated the role of MYCN in regulating the protein cargo of extracellular vesicles (EVs) secreted by tumour cells that can be internalized by recipient cells with functional consequences. Using a switchable MYCN system coupled to mass spectrometry analysis, we found that MYCN regulates distinct sets of proteins in the EVs secreted by neuroblastoma cells. EVs produced by MYCN-expressing cells or isolated from neuroblastoma patients induced the Warburg effect, proliferation and c-MYC expression in target cells. Mechanistically, we linked the cancer-promoting activity of EVs to the glycolytic kinase pyruvate kinase M2 (PKM2) that was enriched in EVs secreted by MYC-expressing neuroblastoma cells. Importantly, the glycolytic enzymes PKM2 and hexokinase II were detected in the EVs circulating in the bloodstream of neuroblastoma patients, but not in those of non-cancer children. We conclude that MYC-activated cancers might spread oncogenic signals to remote body locations through EVs.

scholarly journals The dynamic side of the Warburg effect: glycolytic intermediate storage as buffer for fluctuating glucose and O2 supply in tumor cells

F1000Research ◽  
2018 ◽  
Vol 7 ◽  
pp. 1177
Author(s):  
Johannes H.G.M. van Beek
Keyword(s):  
Blood Flow ◽  
Glucose Uptake ◽  
Tumor Cells ◽  
High Glucose ◽  
Warburg Effect ◽  
Low Flow ◽  
Glycolytic Intermediate ◽  
Head Section ◽  
Glycolytic Intermediates ◽  
The Warburg Effect

Background: Tumor cells often show altered metabolism which supports uncontrolled proliferation. A classic example is the Warburg effect: high glucose uptake and lactate production despite sufficient oxygen supply. Remarkably, tumor cells can transiently take up glucose even an order of magnitude faster when glucose is reintroduced after depletion. Regulation and significance of this high glucose uptake are investigated here. Methods: A new computational model was developed which reproduces two types of experimental data on Ehrlich ascites tumor cells: measurements by Otto Warburg of the average aerobic glycolytic rate during one hour (Warburg effect), and fast metabolic responses measured by others during the first minutes after reintroducing glucose. The model is subsequently extended with equations for glucose and O2 transport to predict the role of metabolism during fluctuations of blood flow in tumor tissue. Results: Model analysis reveals dynamic regulation of the head section of glycolysis where glucose uptake and phosphorylation occur. The head section is disinhibited slowly when concentrations of glycolytic intermediates fall, causing glucose uptake rate to considerably exceed that found by Warburg. The head section is partially inhibited in about a minute when sufficient glucose has been taken up. Simulations predict that tumors greedily take up glucose when blood flow resumes after periods of low flow. The cells then store glucose as fructose 1,6-bisphosphate and other glycolytic intermediates. During subsequent periods of low flow that cause O2 and glucose depletion these stores are used for ATP production and biomass. Conclusions: The powerful glycolytic system in tumors not only synthesizes ATP at high steady rates, but can also store glycolytic intermediates to buffer temporary oxygen and nutrient shortages for up to 10 minutes. The head section of glycolysis in tumor cells, disinhibited during glucose shortages, becomes very efficient at stealing glucose from other cells, even at low glucose concentrations.

scholarly journals Reactive Oxygen Species and Metabolic Re-Wiring in Acute Leukemias

2021 ◽  
Author(s):  
Andrew J. Robinson ◽  
Richard L. Darley ◽  
Alex Tonks
Keyword(s):  
Reactive Oxygen Species ◽  
Warburg Effect ◽  
Cellular Proliferation ◽  
Aerobic Glycolysis ◽  
Cell Signalling ◽  
Reactive Oxygen ◽  
Metabolic Reprogramming ◽  
Oxygen Species ◽  
Acute Leukemias ◽  
The Warburg Effect

Reactive oxygen species (ROS) is the collective term for several oxygen containing free radicals, such as hydrogen peroxide. ROS is important in innate immunity, protein folding in the endoplasmic reticulum and as a cell signalling molecule involved in cellular proliferation, survival, differentiation, and gene expression. ROS has been implicated in both hematopoietic stem cell quiescence and hematopoietic differentiation. Consequently, ROS is of considerable interest as a therapeutic target, with both pro-oxidant and anti-oxidant cellular modulation being explored. Recently, it has been established that increased ROS production in acute myeloid leukemia (AML) leads to increased glycolysis and metabolic reprogramming. It is often stated as a key tenet of the Warburg effect, that transformed cells, including AML, show increased aerobic glycolysis accompanied by increased cellular glucose uptake and lactate secretion. This review will summarize ROS state of the art in acute leukemia and how these reactive molecules re-wire metabolism in cancer cells. The review will focus on what are ROS? What are the sources of ROS in hematopoietic cells and their function and how this relates to the Warburg effect and regulation of metabolic pathways in acute leukemias.

scholarly journals The Warburg effect is necessary to promote glycosylation in the blastema during zebrafish tail regeneration

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Jason W. Sinclair ◽  
David R. Hoying ◽  
Erica Bresciani ◽  
Damian Dalle Nogare ◽  
Carli D. Needle ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Warburg Effect ◽  
High Capacity ◽  
Cell Types ◽  
Pentose Phosphate ◽  
Metabolic Reprogramming ◽  
Tail Regeneration ◽  
Hexosamine Biosynthetic Pathway ◽  
Genetic Ablation ◽  
The Warburg Effect

AbstractThroughout their lifetime, fish maintain a high capacity for regenerating complex tissues after injury. We utilized a larval tail regeneration assay in the zebrafish Danio rerio, which serves as an ideal model of appendage regeneration due to its easy manipulation, relatively simple mixture of cell types, and superior imaging properties. Regeneration of the embryonic zebrafish tail requires development of a blastema, a mass of dedifferentiated cells capable of replacing lost tissue, a crucial step in all known examples of appendage regeneration. Using this model, we show that tail amputation triggers an obligate metabolic shift to promote glucose metabolism during early regeneration similar to the Warburg effect observed in tumor forming cells. Inhibition of glucose metabolism did not affect the overall health of the embryo but completely blocked the tail from regenerating after amputation due to the failure to form a functional blastema. We performed a time series of single-cell RNA sequencing on regenerating tails with and without inhibition of glucose metabolism. We demonstrated that metabolic reprogramming is required for sustained TGF-β signaling and blocking glucose metabolism largely mimicked inhibition of TGF-β receptors, both resulting in an aberrant blastema. Finally, we showed using genetic ablation of three possible metabolic pathways for glucose, that metabolic reprogramming is required to provide glucose specifically to the hexosamine biosynthetic pathway while neither glycolysis nor the pentose phosphate pathway were necessary for regeneration.

The warburg effect and tumour cell survival in human GBMs

2007 ◽  
Vol 30 (4) ◽  
pp. 97 ◽  
Author(s):  
A Wolf ◽  
J Mukherjee ◽  
A Guha
Keyword(s):  
Cytochrome C ◽  
Cell Survival ◽  
Expression Profile ◽  
Tumour Cell ◽  
Warburg Effect ◽  
Glycolytic Enzymes ◽  
Cytochrome C Release ◽  
Apoptotic Pathway ◽  
The Warburg Effect

Introduction: GBMs are resistant to apoptosis induced by the hypoxic microenvironment and standard therapies including radiation and chemotherapy. We postulate that the Warburg effect, a preferential glycolytic phenotype of tumor cells even under aerobic conditions, plays a role in these aberrant pro-survival signals. In this study we quantitatively examined the expression profile of hypoxia-related glycolytic genes within pathologically- and MRI-defined “centre” and “periphery” of GBMs. We hypothesize that expression of hypoxia-induced glycolytic genes, particularly hexokinase 2 (HK2), favours cell survival and modulates resistance to tumour cell apoptosis by inhibiting the intrinsic mitochondrial apoptotic pathway. Methods: GBM patients underwent conventional T1-weighted contrast-enhanced MRI and MR spectroscopy studies on a 3.0T GE scanner, prior to stereotactic sampling (formalin and frozen) from regions which were T1-Gad enhancing (“centre”) and T2-positive, T1-Gad negative (“periphery”). Real-time qRT-PCR was performed to quantify regional gene expression of glycolytic genes including HK2. In vitro functional studies were performed in U87 and U373 GBM cell lines grown in normoxic (21% pO2) and hypoxic (< 1%pO2) conditions, transfected with HK2 siRNA followed by measurement of cell proliferation (BrdU), apoptosis (activated caspase 3/7, TUNEL, cytochrome c release) and viability (MTS assay). Results: There exists a differential expression profile of glycolytic enzymes between the hypoxic center and relatively normoxic periphery of GBMs. Under hypoxic conditions, there is increased expression of HK2 at the mitochondrial membrane in GBM cells. In vitro HK2 knockdown led to decreased cell survival and increased apoptosis via the intrinsic mitochondrial pathway, as seen by increased mitochondrial release of cytochrome-C. Conclusions: Increased expression of HK2 in the centre of GBMs promotes cell survival and confers resistance to apoptosis, as confirmed by in vitro studies. In vivo intracranial xenograft studies with injection of HK2-shRNA are currently being performed. HK2 and possibly other glycolytic enzymes may provide a target for enhanced therapeutic responsiveness thereby improving prognosis of patients with GBMs.

Phytometabolites Targeting the Warburg Effect in Cancer Cells: A Mechanistic Review

2017 ◽  
Vol 18 (9) ◽  
Author(s):  
Mohadeseh Hasanpourghadi ◽  
Chung Yeng Looi ◽  
Ashok Kumar Pandurangan ◽  
Gautam Sethi ◽  
Won Fen Wong ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Warburg Effect ◽  
The Warburg Effect

Metabolic reprogramming for cancer cells and their microenvironment: Beyond the Warburg Effect

2018 ◽  
Vol 1870 (1) ◽  
pp. 51-66 ◽  
Author(s):  
Linchong Sun ◽  
Caixia Suo ◽  
Shi-ting Li ◽  
Huafeng Zhang ◽  
Ping Gao
Keyword(s):  
Cancer Cells ◽  
Warburg Effect ◽  
Metabolic Reprogramming ◽  
The Warburg Effect

scholarly journals Refractory Hyperlactatemia and Hypoglycemia in an Adult with Non-Hodgkin’s Lymphoma: A Case Report and Review of the Warburg Effect

2021 ◽  
pp. 1159-1167
Author(s):  
Zainab Al Maqrashi ◽  
Mary Sedarous ◽  
Avinash Pandey ◽  
Catherine Ross ◽  
Ahraaz Wyne
Keyword(s):  
Lactic Acidosis ◽  
Warburg Effect ◽  
Hodgkin’S Lymphoma ◽  
Abdominal Mass ◽  
Hodgkin's Lymphoma ◽  
Type B ◽  
Elderly Male ◽  
Non Hodgkin’S Lymphoma ◽  
Non Hodgkin's Lymphoma ◽  
The Warburg Effect

Lactate is a byproduct of anaerobic glycolysis, and hyperlactatemia is commonly seen in critically ill patients. We report a case of an elderly male presenting with undifferentiated constitutional symptoms, anemia, thrombocytopenia, severe lactic acidosis, refractory hypoglycemia, and a newly detected abdominal mass. A dedicated workup ruled out infectious etiologies and revealed metastatic non-Hodgkin’s lymphoma. This study explores etiologies of type B lactic acidosis in oncology patients, with a focus on Warburg’s effect, and its potential for prognostication.

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