Cancer Signaling Drives Cancer Metabolism: AKT and the Warburg Effect

2021 ◽  
Vol 81 (19) ◽  
pp. 4896-4898
Author(s):  
Aaron M. Hosios ◽  
Brendan D. Manning
Keyword(s):  
Warburg Effect ◽  
Cancer Metabolism ◽  
Cancer Signaling ◽  
The Warburg Effect

scholarly journals Proton export drives the Warburg Effect

2021 ◽  
Author(s):  
Shonagh Russell ◽  
Liping Xu ◽  
Yoonseok Kam ◽  
Dominique Abrahams ◽  
Bryce Ordway ◽  
...  
Keyword(s):  
Warburg Effect ◽  
Cancer Metabolism ◽  
Aerobic Glycolysis ◽  
Lactate Production ◽  
Glycolytic Enzymes ◽  
Hek293 Cells ◽  
Driver Mutations ◽  
The Warburg Effect

Aggressive cancers commonly ferment glucose to lactic acid at high rates, even in the presence of oxygen. This is known as aerobic glycolysis, or the “Warburg Effect”. It is widely assumed that this is a consequence of the upregulation of glycolytic enzymes. Oncogenic drivers can increase the expression of most proteins in the glycolytic pathway, including the terminal step of exporting H+ equivalents from the cytoplasm. Proton exporters maintain an alkaline cytoplasmic pH, which can enhance all glycolytic enzyme activities, even in the absence of oncogene-related expression changes. Based on this observation, we hypothesized that increased uptake and fermentative metabolism of glucose could be driven by the expulsion of H+ equivalents from the cell. To test this hypothesis, we stably transfected lowly-glycolytic MCF-7, U2-OS, and glycolytic HEK293 cells to express proton exporting systems: either PMA1 (yeast H+-ATPase) or CAIX (carbonic anhydrase 9). The expression of either exporter in vitro enhanced aerobic glycolysis as measured by glucose consumption, lactate production, and extracellular acidification rate. This resulted in an increased intracellular pH, and metabolomic analyses indicated that this was associated with an increased flux of all glycolytic enzymes upstream of pyruvate kinase. These cells also demonstrated increased migratory and invasive phenotypes in vitro, and these were recapitulated in vivo by more aggressive behavior, whereby the acid-producing cells formed higher grade tumors with higher rates of metastases. Neutralizing tumor acidity with oral buffers reduced the metastatic burden. Therefore, cancer cells with increased H+ export increase intracellular alkalization, even without oncogenic driver mutations, and this is sufficient to alter cancer metabolism towards a Warburg phenotype.

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.

Targeting Key Transporters in Tumor Glycolysis as a Novel Anticancer Strategy

2018 ◽  
Vol 18 (6) ◽  
pp. 454-466 ◽  
Author(s):  
Yunli Shi ◽  
Shengnan Liu ◽  
Shabir Ahmad ◽  
Qingzhi Gao
Keyword(s):  
Anticancer Agents ◽  
Warburg Effect ◽  
Drug Transport ◽  
Cancer Metabolism ◽  
Underlying Mechanism ◽  
Drug Uptake ◽  
Metabolic Characteristics ◽  
Current Scenario ◽  
Theranostic Agents ◽  
The Warburg Effect

Increased glycolysis has been one of the metabolic characteristics known as the Warburg effect. The functional and therapeutic importance of the Warburg effect in targeted therapy is scientifically recognized and the glucose metabolic pathway has become a desirable target of anticancer strategies. Glucose transporters (GLUTs) play an important role in cancer glycolysis to sustain cancer cell proliferation, metastasis and survival. Utilizing the knowledge of differential expression and biological functions of GLUTs offers us the possibility of designing and delivering chemotherapeutics toward targeted tumor tissues for improved cancer selectivity. Inhibition of glucose uptake or glycolysis may effectively kill hypoxic cancer cells. Facilitative drug uptake via active transportation provides the potential opportunity to circumvent the drug resistance in chemotherapy. GLUTs as the hallmarks and biotargets of cancer metabolism enable the design and development of novel targeted theranostic agents. In this updated review, we examine the current scenario of the GLUTs as strategic targets in cancer and the unique concepts for discovery and development of GLUTs-targeted anticancer agents. We highlight the recent progresses on structural biology and underlying mechanism studies of GLUTs, with a brief introduction to the computational approaches in GLUT-mediated drug transport and tumor targeting.

scholarly journals Cancer metabolism in space and time: Beyond the Warburg effect

2017 ◽  
Vol 1858 (8) ◽  
pp. 556-572 ◽  
Author(s):  
Pierre Danhier ◽  
Piotr Bański ◽  
Valéry L Payen ◽  
Debora Grasso ◽  
Luigi Ippolito ◽  
...  
Keyword(s):  
Warburg Effect ◽  
Cancer Metabolism ◽  
Space And Time ◽  
The Warburg Effect

scholarly journals Extracellular citrate and metabolic adaptations of cancer cells

2021 ◽  
Author(s):  
E. Kenneth Parkinson ◽  
Jerzy Adamski ◽  
Grit Zahn ◽  
Andreas Gaumann ◽  
Fabian Flores-Borja ◽  
...  
Keyword(s):  
Oxidative Phosphorylation ◽  
Cancer Cells ◽  
Immune Cells ◽  
Warburg Effect ◽  
Cancer Metabolism ◽  
Krebs Cycle ◽  
Therapy Resistance ◽  
Tumour Microenvironment ◽  
The Warburg Effect

Abstract It is well established that cancer cells acquire energy via the Warburg effect and oxidative phosphorylation. Citrate is considered to play a crucial role in cancer metabolism by virtue of its production in the reverse Krebs cycle from glutamine. Here, we review the evidence that extracellular citrate is one of the key metabolites of the metabolic pathways present in cancer cells. We review the different mechanisms by which pathways involved in keeping redox balance respond to the need of intracellular citrate synthesis under different extracellular metabolic conditions. In this context, we further discuss the hypothesis that extracellular citrate plays a role in switching between oxidative phosphorylation and the Warburg effect while citrate uptake enhances metastatic activities and therapy resistance. We also present the possibility that organs rich in citrate such as the liver, brain and bones might form a perfect niche for the secondary tumour growth and improve survival of colonising cancer cells. Consistently, metabolic support provided by cancer-associated and senescent cells is also discussed. Finally, we highlight evidence on the role of citrate on immune cells and its potential to modulate the biological functions of pro- and anti-tumour immune cells in the tumour microenvironment. Collectively, we review intriguing evidence supporting the potential role of extracellular citrate in the regulation of the overall cancer metabolism and metastatic activity.

scholarly journals Macrosphelide A Exhibits a Specific Anti-Cancer Effect by Simultaneously Inactivating ENO1, ALDOA, and FH

2021 ◽  
Vol 14 (10) ◽  
pp. 1060
Author(s):  
Kyoung Song ◽  
Nirmal Rajasekaran ◽  
Chaithanya Chelakkot ◽  
Hunseok Lee ◽  
Seungmann Paek ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Warburg Effect ◽  
Cancer Metabolism ◽  
Aerobic Glycolysis ◽  
Fumarate Hydratase ◽  
Metabolic Adaptation ◽  
Normal Cells ◽  
Target Proteins ◽  
Anti Cancer ◽  
The Warburg Effect

Aerobic glycolysis in cancer cells, also known as the Warburg effect, is an indispensable hallmark of cancer. This metabolic adaptation of cancer cells makes them remarkably different from normal cells; thus, inhibiting aerobic glycolysis is an attractive strategy to specifically target tumor cells while sparing normal cells. Macrosphelide A (MSPA), an organic small molecule, is a potential lead compound for the design of anti-cancer drugs. However, its role in modulating cancer metabolism remains poorly understood. MSPA target proteins were screened using mass spectrometry proteomics combined with affinity chromatography. Direct and specific interactions of MSPA with its candidate target proteins were confirmed by in vitro binding assays, competition assays, and simulation modeling. The siRNA-based knockdown of MSPA target proteins indirectly confirmed the cytotoxic effect of MSPA in HepG2 and MCF-7 cancer cells. In addition, we showed that MSPA treatment in the HEPG2 cell line significantly reduced glucose consumption and lactate release. MSPA also inhibited cancer cell proliferation and induced apoptosis by inhibiting critical enzymes involved in the Warburg effect: aldolase A (ALDOA), enolase 1 (ENO1), and fumarate hydratase (FH). Among these enzymes, the purified ENO1 inhibitory potency of MSPA was further confirmed to demonstrate the direct inhibition of enzyme activity to exclude indirect/secondary factors. In summary, MSPA exhibits anti-cancer effects by simultaneously targeting ENO1, ALDOA, and FH.

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].

Cancer metabolism and the Warburg effect: the role of HIF-1 and PI3K

2015 ◽  
Vol 42 (4) ◽  
pp. 841-851 ◽  
Author(s):  
Rupert Courtnay ◽  
Darleen C. Ngo ◽  
Neha Malik ◽  
Katherine Ververis ◽  
Stephanie M. Tortorella ◽  
...  
Keyword(s):  
Warburg Effect ◽  
Cancer Metabolism ◽  
The Warburg Effect
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