scholarly journals Activating oxidative phosphorylation by a pyruvate dehydrogenase kinase inhibitor overcomes sorafenib resistance of hepatocellular carcinoma

2012 ◽  
Vol 108 (1) ◽  
pp. 72-81 ◽  
Author(s):  
Y-C Shen ◽  
D-L Ou ◽  
C Hsu ◽  
K-L Lin ◽  
C-Y Chang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Oxidative Phosphorylation ◽  
Pyruvate Dehydrogenase ◽  
Kinase Inhibitor ◽  
Pyruvate Dehydrogenase Kinase

Abstract 331: Recovery of Mitochondrial Bioenergetics after Hypoxia via Regulating Pyruvate Dehydrogenase Kinase and Adenosine Monophosphate-activated Kinase

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Jessica M Toli ◽  
Minzhen He ◽  
Carolyn Suzuki ◽  
Maha Abdellatif
Keyword(s):  
Fatty Acid ◽  
Oxidative Phosphorylation ◽  
Cardiac Myocytes ◽  
Pyruvate Dehydrogenase ◽  
Pyruvate Dehydrogenase Kinase ◽  
Neonatal Rat ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Mitochondrial Bioenergetics ◽  
Peroxisome Proliferator Activated Receptor

Mitochondrial quality control is critical for the survival of cardiac myocytes during stress. The purpose of this study was to examine the effect of metabolic substrates and regulators of metabolism on mitochondrial bioenergetics, as an indicator of mitochondrial quality, and how these factors might influence the recovery of the cell’s bioenergetics after hypoxia/ischemia. By monitoring oxygen consumption rates (OCR), in real-time, in live neonatal rat myocytes and human cardiac myocyte-differentiated induced pluripotent stem cells, we found that both cell types can maintain basal OCR efficiently with any metabolic substrate; however, the neonatal cells require both glucose and fatty acid, while the human adult cells require fatty acid only, for mounting maximum reserve respiratory capacity (RRC). Our data also show that subjecting cardiac myocytes to hypoxia results in a reduction of the cells’ basal OCR and oxidative phosphorylation, and exhausts the RRC, which is accompanied by an increase in pyruvate dehydrogenase kinase (Pdk) 1 and 4. Except for normalization of Pdk1 levels, there was little or no recovery of these parameters after reoxygenation. We, thus, hypothesized, that inhibition of Pdks may help recovery of the cell’s bioenergetics. Indeed, our results show that by inhibiting Pdks with dichloroacetate (DCA) before or after hypoxia, the cells’ bioenergetics, including OCR, oxidative phosphorylation, and RRC in neonatal myocytes, and RRC in the human myocytes fully recover within 24 h. On the other hand, activating AMP-activated kinase (AMPK) resulted in delayed (96 h) improvement of the cells’ RRC that was accompanied by an increase in peroxisome proliferator-activated receptor gamma, coactivator 1α (3.5x), peroxisome proliferator-activated receptor-α (2x), and mitochondrial number (2x). These results led us to conclude that compromised mitochondrial quality can be rescued through mechanisms that regulate glucose or fatty acid oxidation by either inhibiting Pdks or activating AMPK, respectively, in rodent and human myocytes.

scholarly journals MiR-130a-3p Regulates the Glycolysis via Targeting PDK1 in Hepatocellular Carcinoma

2021 ◽  
Author(s):  
Hai-Long Li ◽  
Jie Shi ◽  
Qi Qi ◽  
Yue Huang ◽  
Chi Liu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Glucose Metabolism ◽  
Pyruvate Dehydrogenase ◽  
Pyruvate Dehydrogenase Kinase ◽  
Luciferase Reporter ◽  
Luciferase Reporter Gene ◽  
And Migration ◽  
Low Expression ◽  
Hcc Cells

Abstract MiR-130a-3p has been certified to have low expression in several types of tumors. However, the function of miR-130a-3p in glucose metabolism and hepatocellular carcinoma progression is still elusive. Here we report that miR-130a-3p has explicitly low expression in human HCC tissues and cells and is closely related to the patient's tumor size and grade. Overexpression of miR-130a-3p significantly inhibits the glucose metabolism, proliferation and migration of HCC cells in vitro. In order to further study the effects of miR-130a-3p in the glucose metabolism of HCC cells, we found that overexpression of miR-130a-3p significantly inhibited the expression of pyruvate dehydrogenase kinase 1 (PDK1). Consistently, we confirmed that PDK1 is the target gene of miR-130a-3p through dual luciferase reporter gene assays. Cell rescue experiments showed that PDK1 inhibitors reversed the enhancement of cell proliferation, migration and glucose metabolism by miR-130a-3p inhibitor in Hep3B cells. In terms of mechanism, overexpression of miR-130a-3p targeted and inhibited the expression of PDK1, after which pyruvate dehydrogenase (PDH) is activated, thus glycolysis is inhibited, the production of lactic acid and ATP is reduced, and the ability to proliferate and migrate in HCC cells is weakened. In conclusion, our study highlights efforts to target PDK1 and miR-130a-3p as potential therapeutic strategies for the treatment of HCC.

scholarly journals ARNT deficiency represses pyruvate dehydrogenase kinase 1 to trigger ROS production and melanoma metastasis

Oncogenesis ◽  
2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Chi-Ruei Huang ◽  
Ting-Wei Chang ◽  
Chung-Ta Lee ◽  
Chih-Jie Shen ◽  
Wen-Chang Chang ◽  
...  
Keyword(s):  
Oxidative Phosphorylation ◽  
Glucose Uptake ◽  
Pyruvate Dehydrogenase ◽  
Metastatic Potential ◽  
Metabolic Changes ◽  
Pyruvate Dehydrogenase Kinase ◽  
Migration And Invasion ◽  
Melanoma Metastasis ◽  
Pyruvate Dehydrogenase Kinase 1 ◽  
Tissue Specimens

AbstractThe metabolic changes in melanoma cells that are required for tumor metastasis have not been fully elucidated. In this study, we show that the increase in glucose uptake and mitochondrial oxidative phosphorylation confers metastatic ability as a result of aryl hydrocarbon receptor nuclear translocator (ARNT) deficiency. In clinical tissue specimens, increased ARNT, pyruvate dehydrogenase kinase 1 (PDK1), and NAD(P)H quinine oxidoreductase-1 (NQO1) was observed in benign nevi, whereas lower expression was observed in melanoma. The depletion of ARNT dramatically repressed PDK1 and NQO1 expression, which resulted in an increase of ROS levels. The elimination of ROS using N-acetylcysteine (NAC) and inhibition of oxidative phosphorylation using carbonyl cyanide m-chlorophenyl hydrazone (CCCP) and rotenone inhibited the ARNT and PDK1 deficiency-induced cell migration and invasion. In addition, ARNT deficiency in tumor cells manipulated the glycolytic pathway through enhancement of the glucose uptake rate, which reduced glucose dependence. Intriguingly, CCCP and NAC dramatically inhibited ARNT and PDK1 deficiency-induced tumor cell extravasation in mouse models. Our work demonstrates that downregulation of ARNT and PDK1 expression serves as a prognosticator, which confers metastatic potential as the metastasizing cells depend on metabolic changes.

Inhibition of mitochondrial pyruvate dehydrogenase kinase: a proposed mechanism by which melatonin causes cancer cells to overcome cytosolic glycolysis, reduce tumor biomass and reverse insensitivity to chemotherapy

2019 ◽  
Vol 2 (3) ◽  
pp. 105-119 ◽  
Author(s):  
Russel J Reiter ◽  
Ramaswamy Sharma ◽  
Qiang Ma ◽  
Sergio Rosales-Corral ◽  
Dario Acuna-Castroviejo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Oxidative Phosphorylation ◽  
Cancer Cells ◽  
Pyruvate Dehydrogenase ◽  
Warburg Effect ◽  
Breast Cancer Cells ◽  
Pyruvate Dehydrogenase Kinase ◽  
Cell Phenotype ◽  
Acetyl Coa ◽  
The Warburg Effect

This review presents a hypothesis to explain the role of melatonin in regulating glucose metabolism in cancer cells.  Many cancer cells use cytosolic glycolysis (the Warburg effect) to produce energy (ATP).  Under these conditions, glucose is primarily converted to lactate which is released into the blood in large quantities. The Warburg effect gives cancer cells advantages in terms of enhanced macromolecule synthesis required for accelerated cellular proliferation, reduced cellular apoptosis which enhances tumor biomass and a greater likelihood of metastasis.  Based on available data, high circulating melatonin levels at night serve as a signal for breast cancer cells to switch from cytosolic glycolysis to mitochondrial glucose oxidation and oxidative phosphorylation for ATP production. In this situation, melatonin promotes the synthesis of acetyl-CoA from pyruvate; we speculate that melatonin does this by inhibiting the mitochondrial enzyme pyruvate dehydrogenase kinase (PDK) which normally inhibits pyruvate dehydrogenase complex (PDC), the enzyme that controls the pyruvate to acetyl-CoA conversion. Acetyl-CoA has several important functions in the mitochondria; it feeds into the citric acid cycle which improves oxidative phosphorylation and, additionally, it is a necessary co-factor for the rate limiting enzyme, arylalkylamine N-acetyltransferase, in mitochondrial melatonin synthesis.  When breast cancer cells are using cytosolic glycolysis (during the day) they are of the cancer phenotype; at night when they are using mitochondria to produce ATP via oxidative phosphorylation, they have a normal cell phenotype. If this day:night difference in tumor cell metabolism is common in other cancers, it indicates that these tumor cells are only cancerous part of the time.  We also speculate that high nighttime melatonin levels also reverse the insensitivity of tumors to chemotherapy.

Mitochondrial metabolism, redox signaling, and fusion: a mitochondria-ROS-HIF-1α-Kv1.5 O2-sensing pathway at the intersection of pulmonary hypertension and cancer

2008 ◽  
Vol 294 (2) ◽  
pp. H570-H578 ◽  
Author(s):  
Stephen L. Archer ◽  
Mardi Gomberg-Maitland ◽  
Michael L. Maitland ◽  
Stuart Rich ◽  
Joe G. N. Garcia ◽  
...  
Keyword(s):  
Pyruvate Dehydrogenase ◽  
Kinase Inhibitor ◽  
De Novo ◽  
Human Cancer ◽  
Hypoxia Inducible Factor ◽  
Experimental Models ◽  
Redox Signaling ◽  
Mitochondrial Metabolism ◽  
Pyruvate Dehydrogenase Kinase ◽  
Mitochondrial Abnormalities

Pulmonary arterial hypertension (PAH) is a lethal syndrome characterized by vascular obstruction and right ventricular failure. Although the fundamental cause remains elusive, many predisposing and disease-modifying abnormalities occur, including endothelial injury/dysfunction, bone morphogenetic protein receptor-2 gene mutations, decreased expression of the O2-sensitive K+ channel (Kv1.5), transcription factor activation [hypoxia-inducible factor-1α (HIF-1α) and nuclear factor-activating T cells], de novo expression of survivin, and increased expression/activity of both serotonin transporters and platelet-derived growth factor receptors. Together, these abnormalities create a cancerlike, proliferative, apoptosis-resistant phenotype in pulmonary artery smooth muscle cells (PASMCs). A possible unifying mechanism for PAH comes from studies of fawn-hooded rats, which manifest spontaneous PAH and impaired O2 sensing. PASMC mitochondria normally produce reactive O2 species (ROS) in proportion to Po2. Superoxide dismutase 2 (SOD2) converts intramitochondrial superoxide to diffusible H2O2, which serves as a redox-signaling molecule, regulating pulmonary vascular tone and structure through effects on Kv1.5 and transcription factors. O2 sensing is mediated by this mitochondria-ROS-HIF-1α-Kv1.5 pathway. In PAH and cancer, mitochondrial metabolism and redox signaling are reversibly disordered, creating a pseudohypoxic redox state characterized by normoxic decreases in ROS, a shift from oxidative to glycolytic metabolism and HIF-1α activation. Three newly recognized mitochondrial abnormalities disrupt the mitochondria-ROS-HIF-1α-Kv1.5 pathway: 1) mitochondrial pyruvate dehydrogenase kinase activation, 2) SOD2 deficiency, and 3) fragmentation and/or hyperpolarization of the mitochondrial reticulum. The pyruvate dehydrogenase kinase inhibitor, dichloroacetate, corrects the mitochondrial abnormalities in experimental models of PAH and human cancer, causing a regression of both diseases. Mitochondrial abnormalities that disturb the ROS-HIF-1α-Kv1.5 O2-sensing pathway contribute to the pathogenesis of PAH and cancer and constitute promising therapeutic targets.

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