scholarly journals Mitochondrial STAT5A promotes metabolic remodeling and the Warburg effect by inactivating the pyruvate dehydrogenase complex

2021 ◽  
Vol 12 (7) ◽  
Author(s):  
Liang Zhang ◽  
Jianong Zhang ◽  
Yan Liu ◽  
Pingzhao Zhang ◽  
Ji Nie ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Pyruvate Dehydrogenase ◽  
Warburg Effect ◽  
Tricarboxylic Acid Cycle ◽  
Pyruvate Dehydrogenase Complex ◽  
Metabolic Remodeling ◽  
Dehydrogenase Complex ◽  
The Warburg Effect

AbstractSignal transducer and activator 5a (STAT5A) is a classical transcription factor that plays pivotal roles in various biological processes, including tumor initiation and progression. A fraction of STAT5A is localized in the mitochondria, but the biological functions of mitochondrial STAT5A remain obscure. Here, we show that STAT5A interacts with pyruvate dehydrogenase complex (PDC), a mitochondrial gatekeeper enzyme connecting two key metabolic pathways, glycolysis and the tricarboxylic acid cycle. Mitochondrial STAT5A disrupts PDC integrity, thereby inhibiting PDC activity and remodeling cellular glycolysis and oxidative phosphorylation. Mitochondrial translocation of STAT5A is increased under hypoxic conditions. This strengthens the Warburg effect in cancer cells and promotes in vitro cell growth under hypoxia and in vivo tumor growth. Our findings indicate distinct pro-oncogenic roles of STAT5A in energy metabolism, which is different from its classical function as a transcription factor.

scholarly journals Resveratrol reverses the Warburg effect by targeting the pyruvate dehydrogenase complex in colon cancer cells

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Elise Saunier ◽  
Samantha Antonio ◽  
Anne Regazzetti ◽  
Nicolas Auzeil ◽  
Olivier Laprévote ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Cancer Cells ◽  
Pyruvate Dehydrogenase ◽  
Warburg Effect ◽  
Pyruvate Dehydrogenase Complex ◽  
Colon Cancer Cells ◽  
Dehydrogenase Complex ◽  
The Warburg Effect

scholarly journals The effects of various anions and cations on the regulation of pyruvate dehydrogenase complex activity from pig kidney cortex

1988 ◽  
Vol 253 (3) ◽  
pp. 819-825 ◽  
Author(s):  
T Pawelczyk ◽  
R A Easom ◽  
M S Olson
Keyword(s):  
Pyruvate Dehydrogenase ◽  
Pyruvate Dehydrogenase Complex ◽  
Maximal Activity ◽  
Hill Coefficient ◽  
Kidney Cortex ◽  
Complex Activity ◽  
Pig Kidney ◽  
Constant Strength ◽  
Dehydrogenase Complex

The activity of pyruvate dehydrogenase complex (PDC) purified from pig kidney cortex was found to be affected by various uni- and bi-valent ions. At a constant strength of 0.13 M at pH 7.8, K+, Na+, Cl-, HCO3- and HPO4(2-) had significant effects on the activity of PDC: Na+, K+ and HPO4(2-) stimulated, but HCO3- and Cl- inhibited. The stimulatory effect of Na+ was mediated by a change in the Vmax. of PDC only, whereas K+ produced an increase in Vmax. and a change in the Hill coefficient (h). The extent of stimulation produced by HPO4(2-)4 on the activity of PDC was dependent on the concentrations of K+ and Na+. Both cations at concentrations higher than 40 mM partially prevented the effect of HPO4(2-)4. Cl- and HCO3- anions decreased the Vmax. of the enzyme and increased the S0.5 for pyruvate. The effects of Na+, K+, Cl-, HPO4(2-) and HCO3- on the activity of PDC were additive. In the presence of 80 mM-K+, 20 mM-Na+, 10 mM-HPO4(2-), 20 mM-Cl- and 20 mM-HCO3- the activity of PDC was increased by 30%, the S0.5 for pyruvate was increased from 75 to 158 microM and h was decreased from 1.3 to 1.1. Under these conditions and at 1.0 mM-pyruvate, the activity of PDC was 80% of the maximal activity achieved in the presence of these ions and 4.5 mM-pyruvate. The present study suggests that PDC may operate under non-saturating concentrations for substrate in vivo.

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.

On the Specificity of the Herbicide Chlorsulfuron in Intact Spinach Chloroplasts

1985 ◽  
Vol 40 (11-12) ◽  
pp. 917-918 ◽  
Author(s):  
Uwe Homeyer ◽  
D. Schulze-Siebert ◽  
G. Schultz
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Fatty Acid Synthesis ◽  
Pyruvate Dehydrogenase ◽  
Pyruvate Dehydrogenase Complex ◽  
Acid Synthesis ◽  
Spinach Chloroplasts ◽  
Transamination Reaction ◽  
Dehydrogenase Complex

Abstract In vitro incubation of intact spinach chloroplasts with 1 mᴍ Pyruvate was used to study the specificity of action of the herbicide Chlorsulfuron on the synthesis of valine, alanine and fatty acids. As a result, increasing concentrations of the herbicide strongly inhibited valine synthesis while fatty acid synthesis via pyruvate dehydrogenase complex (PDC) and alanine formation by transamination reaction was promoted.

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