scholarly journals The Implications of PDK1–4 on Tumor Energy Metabolism, Aggressiveness and Therapy Resistance

2020 ◽  
Vol 10 ◽  
Author(s):  
Emine Atas ◽  
Monika Oberhuber ◽  
Lukas Kenner
Keyword(s):  
Pyruvate Dehydrogenase ◽  
De Novo ◽  
Pyruvate Dehydrogenase Complex ◽  
Acid Synthesis ◽  
Therapy Resistance ◽  
Pyruvate Dehydrogenase Kinase ◽  
Metabolic Shift ◽  
Cytotoxic Effects ◽  
Glycolytic Activity ◽  
Energetic State

A metabolic shift from oxidative phosphorylation (OXPHOS) to glycolysis—known as the Warburg effect—is characteristic for many cancers. It gives the cancer cells a survival advantage in the hypoxic tumor microenvironment and protects them from cytotoxic effects of oxidative damage and apoptosis. The main regulators of this metabolic shift are the pyruvate dehydrogenase complex and pyruvate dehydrogenase kinase (PDK) isoforms 1–4. PDK is known to be overexpressed in several cancers and is associated with bad prognosis and therapy resistance. Whereas the expression of PDK1–3 is tissue specific, PDK4 expression is dependent on the energetic state of the whole organism. In contrast to other PDK isoforms, not only oncogenic, but also tumor suppressive functions of PDK4 have been reported. In tumors that profit from high OXPHOS and high de novo fatty acid synthesis, PDK4 can have a protective effect. This is the case for prostate cancer, the most common cancer in men, and makes PDK4 an interesting therapeutic target. While most work is focused on PDK in tumors characterized by high glycolytic activity, little research is devoted to those cases where PDK4 acts protective and is therefore highly needed.

scholarly journals Effects of recombinant monokines on hepatic pyruvate dehydrogenase, pyruvate dehydrogenase kinase, lipogenesis de novo and plasma triacylglycerols. Abolition by prior fasting

1992 ◽  
Vol 284 (1) ◽  
pp. 129-135 ◽  
Author(s):  
M Blackham ◽  
D Cesar ◽  
O J Park ◽  
T C Vary ◽  
K Wu ◽  
...  
Keyword(s):  
Pyruvate Dehydrogenase ◽  
De Novo ◽  
Pyruvate Dehydrogenase Complex ◽  
Interleukin 1 ◽  
Covalent Modification ◽  
Pyruvate Dehydrogenase Kinase ◽  
Hepatic Lipogenesis ◽  
Necrosis Factor Alpha ◽  
Intravenous Glucose ◽  
Ad Libitum

1. The effects of recombinant human tumour necrosis factor alpha (TNF) and murine interleukin-1 alpha (IL-1) on the activation state of the hepatic pyruvate dehydrogenase complex (PDHa), the activity of mitochondrial PDH kinase, hepatic lipogenesis de novo and plasma triacylglycerol (TG) concentrations were studied. 2. Monokine effects depended upon prior nutritional state. In rats fasted for 20 h or 45 h before monokine administration and refeeding (orally or with intravenous glucose), PDHa, TG and hepatic lipogenesis were not increased. In rats fed ad libitum, treatment with TNF plus IL-1 increased the contribution of hepatic lipogenesis to circulating TG to 550% of control values (P = 0.03) and plasma TG concentrations to 159% (P = 0.02), whereas PDHa increased slightly to 120% (P = 0.02) and liver glycogen content fell to 45.8% (P = 0.05) of control values. 3. Intrinsic hepatic PDH kinase activity was not changed by monokine treatment in rats fed ad libitum. 4. The increased lipogenesis de novo showed no correlation (r2 = 0.05, not significant) with hepatic PDHa in individual animals fed ad libitum. 5. In conclusion, these results suggest that monokines increase pyruvate flux through hepatic PDH in vivo in rats fed ad libitum primarily by mechanisms other than covalent modification of PDH. Prior nutritional status exerts a permissive effect for monokine stimulation of PDHa and lipogenesis, consistent with a substrate-mediated action, but the mechanism of this permissive effect remains uncertain.

scholarly journals Anti-Warburg Effect of Melatonin: A Proposed Mechanism to Explain its Inhibition of Multiple Diseases

2021 ◽  
Vol 22 (2) ◽  
pp. 764
Author(s):  
Russel J. Reiter ◽  
Ramaswamy Sharma ◽  
Sergio Rosales-Corral
Keyword(s):  
Pyruvate Dehydrogenase ◽  
Warburg Effect ◽  
Coenzyme A ◽  
Aerobic Glycolysis ◽  
Pyruvate Dehydrogenase Complex ◽  
Pyruvate Dehydrogenase Kinase ◽  
Metabolic Phenotype ◽  
Common Denominator ◽  
Acetyl Coenzyme A ◽  
Acetyl Coenzyme

Glucose is an essential nutrient for every cell but its metabolic fate depends on cellular phenotype. Normally, the product of cytosolic glycolysis, pyruvate, is transported into mitochondria and irreversibly converted to acetyl coenzyme A by pyruvate dehydrogenase complex (PDC). In some pathological cells, however, pyruvate transport into the mitochondria is blocked due to the inhibition of PDC by pyruvate dehydrogenase kinase. This altered metabolism is referred to as aerobic glycolysis (Warburg effect) and is common in solid tumors and in other pathological cells. Switching from mitochondrial oxidative phosphorylation to aerobic glycolysis provides diseased cells with advantages because of the rapid production of ATP and the activation of pentose phosphate pathway (PPP) which provides nucleotides required for elevated cellular metabolism. Molecules, called glycolytics, inhibit aerobic glycolysis and convert cells to a healthier phenotype. Glycolytics often function by inhibiting hypoxia-inducible factor-1α leading to PDC disinhibition allowing for intramitochondrial conversion of pyruvate into acetyl coenzyme A. Melatonin is a glycolytic which converts diseased cells to the healthier phenotype. Herein we propose that melatonin’s function as a glycolytic explains its actions in inhibiting a variety of diseases. Thus, the common denominator is melatonin’s action in switching the metabolic phenotype of cells.

scholarly journals Evidence for existence of tissue-specific regulation of the mammalian pyruvate dehydrogenase complex

1998 ◽  
Vol 329 (1) ◽  
pp. 191-196 ◽  
Author(s):  
Melissa M. BOWKER-KINLEY ◽  
I. Wilhelmina DAVIS ◽  
Pengfei WU ◽  
A. Robert HARRIS ◽  
M. Kirill POPOV
Keyword(s):  
Tissue Distribution ◽  
Pyruvate Dehydrogenase ◽  
Pyruvate Dehydrogenase Complex ◽  
Pyruvate Dehydrogenase Kinase ◽  
Synthetic Analogue ◽  
Complex Activity ◽  
Acetyl Coa ◽  
Tissue Specific ◽  
Specific Regulation ◽  
Dehydrogenase Complex

Tissue distribution and kinetic parameters for the four isoenzymes of pyruvate dehydrogenase kinase (PDK1, PDK2, PDK3 and PDK4) identified thus far in mammals were analysed. It appeared that expression of these isoenzymes occurs in a tissue-specific manner. The mRNA for isoenzyme PDK1 was found almost exclusively in rat heart. The mRNA for PDK3 was most abundantly expressed in rat testis. The message for PDK2 was present in all tissues tested but the level was low in spleen and lung. The mRNA for PDK4 was predominantly expressed in skeletal muscle and heart. The specific activities of the isoenzymes varied 25-fold, from 50 nmol/min per mg for PDK2 to 1250 nmol/min per mg for PDK3. Apparent Ki values of the isoenzymes for the synthetic analogue of pyruvate, dichloroacetate, varied 40-fold, from 0.2 mM for PDK2 to 8 mM for PDK3. The isoenzymes were also different with respect to their ability to respond to NADH and NADH plus acetyl-CoA. NADH alone stimulated the activities of PDK1 and PDK2 by 20 and 30% respectively. NADH plus acetyl-CoA activated these isoenzymes nearly 200 and 300%. Under comparable conditions, isoenzyme PDK3 was almost completely unresponsive to NADH, and NADH plus acetyl-CoA caused inhibition rather than activation. Isoenzyme PDK4 was activated almost 2-fold by NADH, but NADH plus acetyl-CoA did not activate above the level seen with NADH alone. These results provide the first evidence that the unique tissue distribution and kinetic characteristics of the isoenzymes of PDK are among the major factors responsible for tissue-specific regulation of the pyruvate dehydrogenase complex activity.

scholarly journals Activation of Liver X Receptor Regulates Substrate Oxidation in White Adipocytes

Endocrinology ◽  
2009 ◽  
Vol 150 (9) ◽  
pp. 4104-4113 ◽  
Author(s):  
Britta M. Stenson ◽  
Mikael Rydén ◽  
Knut R. Steffensen ◽  
Kerstin Wåhlén ◽  
Amanda T. Pettersson ◽  
...  
Keyword(s):  
Pyruvate Dehydrogenase ◽  
Pyruvate Dehydrogenase Complex ◽  
Substrate Oxidation ◽  
Pyruvate Dehydrogenase Kinase ◽  
Tissue Mass ◽  
Metabolic Complications ◽  
Pyruvate Dehydrogenase Kinase 4 ◽  
White Adipocytes ◽  
X Receptors

Abstract Liver X receptors (LXRs) are nuclear receptors with established roles in cholesterol, lipid, and carbohydrate metabolism, although their function in adipocytes is not well characterized. Increased adipose tissue mass in obesity is associated with increased adipocyte lipolysis. Fatty acids (FA) generated by lipolysis can be oxidized by mitochondrial β-oxidation, reesterified, or released from the adipocyte. The latter results in higher circulating levels of free FAs, in turn causing obesity-related metabolic complications. However, mitochondrial β-oxidation can at least in part counteract an increased output of FA into circulation. In this study, we provide evidence that activation of LXRs up-regulates mitochondrial β-oxidation in both human and murine white adipocytes. We also show that the expression of a kinase regulating the cellular fuel switch, pyruvate dehydrogenase kinase 4 (PDK4), is up-regulated by the LXR agonist GW3965 in both in vitro differentiated human primary adipocytes and differentiated murine 3T3-L1 cells. Moreover, activation of LXR causes PDK4-dependent phosphorylation of the pyruvate dehydrogenase complex, thereby decreasing its activity and attenuating glucose oxidation. The specificity of the GW3965 effect on oxidation was confirmed by RNA interference targeting LXRs. We propose that LXR has an important role in the regulation of substrate oxidation and the switch between lipids and carbohydrates as cellular fuel in both human and murine white adipocytes.

scholarly journals Targeting Altered Energy Metabolism in Colorectal Cancer: Oncogenic Reprogramming, the Central Role of the TCA Cycle and Therapeutic Opportunities

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1731 ◽  
Author(s):  
Carina Neitzel ◽  
Philipp Demuth ◽  
Simon Wittmann ◽  
Jörg Fahrer
Keyword(s):  
Colorectal Cancer ◽  
Energy Metabolism ◽  
Pyruvate Dehydrogenase ◽  
Pyruvate Dehydrogenase Complex ◽  
Tca Cycle ◽  
Dietary Factors ◽  
Pyruvate Dehydrogenase Kinase ◽  
Driver Mutations ◽  
The Tca Cycle

Colorectal cancer (CRC) is among the most frequent cancer entities worldwide. Multiple factors are causally associated with CRC development, such as genetic and epigenetic alterations, inflammatory bowel disease, lifestyle and dietary factors. During malignant transformation, the cellular energy metabolism is reprogrammed in order to promote cancer cell growth and proliferation. In this review, we first describe the main alterations of the energy metabolism found in CRC, revealing the critical impact of oncogenic signaling and driver mutations in key metabolic enzymes. Then, the central role of mitochondria and the tricarboxylic acid (TCA) cycle in this process is highlighted, also considering the metabolic crosstalk between tumor and stromal cells in the tumor microenvironment. The identified cancer-specific metabolic transformations provided new therapeutic targets for the development of small molecule inhibitors. Promising agents are in clinical trials and are directed against enzymes of the TCA cycle, including isocitrate dehydrogenase, pyruvate dehydrogenase kinase, pyruvate dehydrogenase complex (PDC) and α-ketoglutarate dehydrogenase (KGDH). Finally, we focus on the α-lipoic acid derivative CPI-613, an inhibitor of both PDC and KGDH, and delineate its anti-tumor effects for targeted therapy.

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.

Increased pyruvate dehydrogenase kinase activity in response to sepsis

1991 ◽  
Vol 260 (5) ◽  
pp. E669-E674 ◽  
Author(s):  
T. C. Vary
Keyword(s):  
Skeletal Muscle ◽  
Pyruvate Dehydrogenase ◽  
Kinase Activity ◽  
Pyruvate Dehydrogenase Complex ◽  
Pyruvate Dehydrogenase Kinase ◽  
Sterile Inflammation ◽  
Stable Factor ◽  
Skeletal Muscle Mitochondria ◽  
Dependent Inactivation ◽  
Significant Difference

The effect of sterile inflammation and sepsis on the proportion of active pyruvate dehydrogenase complex (PDH) in mitochondria isolated from skeletal muscle has been investigated. The proportion of active PDH in mitochondria isolated from septic animals was significantly reduced compared with control under all incubation conditions examined, even in the presence of inhibitors of the PDH kinase. There was no significant difference between control and sterile inflammation in any of the incubations examined. The rate constant for ATP-dependent inactivation of the PDH complex in mitochondrial extracts from control animals was -0.42 min-1 (r = 0.993; P less than 0.001) and was not altered in mitochondrial extracts from sterile inflammatory animals (-0.43 min-1; r = 0.999; P less than 0.001). However, rate constants for inactivation in septic animals was significantly increased over twofold to -1.08 min-1 (r = 0.987; P less than 0.001) (P less than 0.001 vs. control or sterile inflammation). In the presence of inhibitors of the PDH kinase reaction (2.5 mM pyruvate or 1 mM dichloroacetate), inactivation of PDH after addition of ATP was significantly greater in mitochondrial extracts from septic than either control or sterile inflammatory animals. These results suggest that sepsis, but not sterile inflammation, induces a stable factor in skeletal muscle mitochondria that increased PDH kinase activity.

Effect of flaxseed oil on muscle protein loss and carbohydrate oxidation impairment in a pig model after lipopolysaccharide challenge

2019 ◽  
Vol 123 (8) ◽  
pp. 859-869
Author(s):  
Ping Kang ◽  
Yang Wang ◽  
Xiangen Li ◽  
Zhicheng Wan ◽  
Xiuying Wang ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Pyruvate Dehydrogenase ◽  
Muscle Protein ◽  
Pyruvate Dehydrogenase Complex ◽  
Plasma Concentrations ◽  
Flaxseed Oil ◽  
Carbohydrate Oxidation ◽  
Pyruvate Dehydrogenase Kinase ◽  
Protein Loss ◽  
Lps Challenge

AbstractFlaxseed oil is rich in α-linolenic acid (ALA), which is the metabolic precursor of EPA and DHA. The present study investigated the effect of flaxseed oil supplementation on lipopolysaccharide (LPS)-induced muscle atrophy and carbohydrate oxidation impairment in a piglet model. Twenty-four weaned pigs were used in a 2 × 2 factorial experiment including dietary treatment (5 % maize oil v. 5 % flaxseed oil) and LPS challenge (saline v. LPS). On day 21 of treatment, the pigs were injected intraperitoneally with 100 μg/kg body weight LPS or sterile saline. At 4 h after injection, blood, gastrocnemius muscle and longissimus dorsi muscle were collected. Flaxseed oil supplementation increased ALA, EPA, total n-3 PUFA contents, protein:DNA ratio and pyruvate dehydrogenase complex quantity in muscles (P < 0·05). In addition, flaxseed oil reduced mRNA expression of toll-like receptor (TLR) 4 and nucleotide-binding oligomerisation domain protein (NOD) 2 and their downstream signalling molecules in muscles and decreased plasma concentrations of TNF-α, IL-6 and IL-8, and mRNA expression of TNF-α, IL-1β and IL-6 (P < 0·05). Moreover, flaxseed oil inclusion increased the ratios of phosphorylated protein kinase B (Akt) 1:total Akt1 and phosphorylated Forkhead box O (FOXO) 1:total FOXO1 and reduced mRNA expression of FOXO1, muscle RING finger (MuRF) 1 and pyruvate dehydrogenase kinase 4 in muscles (P < 0·05). These results suggest that flaxseed oil might have a positive effect on alleviating muscle protein loss and carbohydrates oxidation impairment induced by LPS challenge through regulation of the TLR4/NOD and Akt/FOXO signalling pathways.

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