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https://www.readbyqxmd.com/read/28208156/oncogenic-role-of-pdk4-in-human-colon-cancer-cells
#1
D Leclerc, D N T Pham, N Lévesque, M Truongcao, W D Foulkes, C Sapienza, R Rozen
BACKGROUND: Cancer cells maintain high rates of glycolysis. Pyruvate dehydrogenase kinases (PDK) contribute to this phenomenon, which favours apoptosis resistance and cellular transformation. We previously reported upregulation of PDK4 in normal mucosa of colorectal cancer (CRC) patients compared with controls and in preneoplastic intestine of our mouse model. Decreased methylation of four consecutive PDK4 CpGs was observed in normal mucosa of patients. Although other members of the PDK family have been investigated for transformation potential, PDK4 has not been extensively studied...
February 16, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/28182733/pyruvate-dehydrogenase-kinase-1-is-essential-for-transplantable-mouse-bone-marrow-hematopoietic-stem-cell-and-progenitor-function
#2
Camilla Halvarsson, Pernilla Eliasson, Jan-Ingvar Jönsson
BACKGROUND: Accumulating evidence suggests that hypoxic areas in the bone marrow are crucial for maintenance of hematopoietic stem cells (HSCs) by supporting a quiescent state of cell cycle and regulating the transplantation capacity of long-term (LT)-HSCs. In addition, HSCs seem to express a metabolic profile of energy production away from mitochondrial oxidative phosphorylation in favor of glycolysis. At oxygen deprivation, hypoxia inducible factor 1α (HIF-1α) is known to induce glycolytic enzymes as well as suppressing mitochondrial energy production by inducing pyruvate dehydrogenase kinase 1 (Pdk1) in most cell types...
2017: PloS One
https://www.readbyqxmd.com/read/28163304/predominant-contribution-of-dgk%C3%AE-over-dgk%C3%AE-in-the-control-of-pkc-pdk-1-regulated-functions-in-t-cells
#3
A Ávila-Flores, J Arranz-Nicolás, E Andrada, D Soutar, I Mérida
Diacylglycerol kinase (DGK)-mediated consumption of the diacylglycerol (DAG) generated in response to antigen recognition is an important mechanism to limit T cell function. Targeting DGK activity presents new opportunities for therapeutic manipulation of the immune response, but assessment of individual DGK functions is complex. T cells express two DGK isoforms, DGKα and DGKζ, and there are no isoform-specific inhibitors. Here we used siRNA-mediated gene silencing in human T cells and DGKα- and DGKζ-deficient mice to define DGK isoform-specific regulation of key signaling pathways during T cell activation...
February 6, 2017: Immunology and Cell Biology
https://www.readbyqxmd.com/read/28163135/a-mechanism-based-pharmacokinetic-enzyme-turnover-model-for-dichloroacetic-acid-auto-inhibition-in-rats
#4
Yu Jiang, Gary Milavetz, Margaret O James, Guohua An
Dichloroacetic acid (DCA), a halogenated organic acid, is a pyruvate dehydrogenase kinase (PDK) inhibitor that has been used to treat congenital or acquired lactic acidosis and is currently in early phase clinical trials for cancer treatment. DCA was found to inhibit its own metabolism by irreversibly inactivating glutathione transferase zeta 1 (GSTZ1-1), resulting in non-linear kinetics and abnormally high accumulation ratio after repeated dosing. In this analysis, a semi-mechanistic pharmacokinetic-enzyme turn over model was developed for the first time to capture DCA auto-inhibition, gastrointestinal region-dependent absorption, and time dependent change in bioavailability in rats...
February 2, 2017: Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28123081/histone-deacetylase-inhibitors-protect-against-pyruvate-dehydrogenase-dysfunction-in-huntington-s-disease
#5
Luana Naia, Teresa Cunha-Oliveira, Joana Rodrigues, Tatiana R Rosenstock, Ana Oliveira, Márcio Ribeiro, Catarina Carmo, Sofia I Oliveira-Sousa, Ana I Duarte, Michael R Hayden, A Cristina Rego
: Transcriptional deregulation and changes in mitochondrial bioenergetics, including pyruvate dehydrogenase (PDH) dysfunction, have been described in Huntington's disease (HD). We previously showed that histone deacetylase inhibitors (HDACi), trichostatin A and sodium butyrate (SB), ameliorate mitochondrial function in cells expressing mutant huntingtin. In this work we investigated the effect of HDACi on regulation of PDH activity in striatal cells derived from HD knock-in mice and YAC128 mice...
January 25, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28109078/3-phosphoinositide-dependent-protein-kinase-1-pdk-1-promotes-migration-and-invasion-in-gastric-cancer-cells-through-activating-the-nf-%C3%AE%C2%BAb-pathway
#6
Ning Wu, Changyu He, Bohui Zhu, Jinling Jiang, Yiwen Chen, Tao Ma
Gastric cancer (GC) is one of the most common cancers and the second leading cause of cancer deaths in the world. Manyfactors were reported involving the progression and development of GC. In this study, we aimed to investigate the correlation of 3-phosphoinositide dependent protein kinase 1 (PDK-1) with cell viability, cell migration, and cell invasion of GC. The expression of PDK-1 was measured in different GC cell lines. Thereafter, the expression of PDK-1 was interfered by small hairpin RNA (shRNA) and then incubated with or without the inhibitor of NF-κB pyrrolidine dithiocarbamate (PDTC)...
January 20, 2017: Oncology Research
https://www.readbyqxmd.com/read/28094552/glucose-metabolism-in-cancer-and-ischemia-possible-therapeutic-consequences-of-the-warburg-effect
#7
Spela Salamon, Eva Podbregar, Peter Kubatka, Dietrich Büsselberg, Martin Caprnda, Radka Opatrilova, Vanda Valentova, Mariusz Adamek, Peter Kruzliak, Matej Podbregar
The Warburg effect states that the main source of energy for cancer cells is not aerobic respiration, but glycolysis-even in normoxia. The shift from one to the other is governed by mutually counteracting enzymes: pyruvate dehydrogenase and pyruvate dehydrogenase kinase (PDK). Anaerobic metabolism of cancer cells promotes cell proliferation, local tissue immunosuppression, resistance to hypoxic conditions, and metastatic processes. By switching glucose back to oxidative metabolism, these effects might be reversed...
January 17, 2017: Nutrition and Cancer
https://www.readbyqxmd.com/read/28093038/metabonomic-strategy-to-the-evaluation-of-chinese-medicine-salvia-miltiorrhiza-and-dalbergia-odorifera-interfering-myocardial-ischemia-reperfusion-injury-in-rats
#8
Fei Mu, Jialin Duan, Haixu Bian, Xiaohu Zhai, Peijin Shang, Rui Lin, Meina Zhao, Dongmei Hu, Ying Yin, Aidong Wen, Miaomiao Xi
Extract of Salvia miltiorrhiza and Dalbergia Odorifera (SM-DOO) has been traditionally used for the prevention and treatment of cardiovascular diseases. However, information regarding the pharmacodyamic material basis and potential mechanism remain unknown. Male Sprague-Dawley rats were divided into four groups: Sham, Model, Diltiazem and SM-DOO group, n=6. Rats were pretreated with homologous drugs for 7 days, then subjected to 30 min of ischemia followed by 180 min of reperfusion. Cardioprotection effects of SM-DOO on myocardial ischemia/reperfusion (MI/R) injury rats were examined by hemodynamic, infarct area, histopathology, biochemical indicators and western blot analysis...
January 16, 2017: Rejuvenation Research
https://www.readbyqxmd.com/read/28040265/pyruvate-dehydrogenase-kinase-4-deficiency-attenuates-cisplatin-induced-acute-kidney-injury
#9
Chang Joo Oh, Chae-Myeong Ha, Young-Keun Choi, Sungmi Park, Mi Sun Choe, Nam Ho Jeoung, Yang Hoon Huh, Hyo-Jeong Kim, Hee-Seok Kweon, Ji-Min Lee, Sun Joo Lee, Jae-Han Jeon, Robert A Harris, Keun-Gyu Park, In-Kyu Lee
Clinical prescription of cisplatin, one of the most widely used chemotherapeutic agents, is limited by its side effects, particularly tubular injury-associated nephrotoxicity. Since details of the underlying mechanisms are not fully understood, we investigated the role of pyruvate dehydrogenase kinase (PDK) in cisplatin-induced acute kidney injury. Among the PDK isoforms, PDK4 mRNA and protein levels were markedly increased in the kidneys of mice treated with cisplatin, and c-Jun N-terminal kinase activation was involved in cisplatin-induced renal PDK4 expression...
December 28, 2016: Kidney International
https://www.readbyqxmd.com/read/28035937/mtorc2-rictor-in-alzheimer-s-disease-and-reversal-of-amyloid-%C3%AE-expression-induced-insulin-resistance-and-toxicity-in-rat-primary-cortical-neurons
#10
Han-Kyu Lee, Bumsup Kwon, Cynthia A Lemere, Suzanne de la Monte, Kyohei Itamura, Austin Y Ha, Henry W Querfurth
Mammalian target of rapamycin complex 1 (mTORC1), a nutrient sensor and central controller of cell growth and proliferation, is altered in various models of Alzheimer's disease (AD). Even less studied or understood in AD is mammalian target of rapamycin complex 2 (mTORC2) that influences cellular metabolism, in part through the regulations of Akt/PKB and SGK. Dysregulation of insulin/PI3K/Akt signaling is another important feature of AD pathogenesis. We found that both total mTORC1 and C2 protein levels and individual C1 and C2 enzymatic activities were decreased in human AD brain samples...
December 30, 2016: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/28018235/modulation-of-muscle-fiber-compositions-in-response-to-hypoxia-via-pyruvate-dehydrogenase-kinase-1
#11
Daniel D Nguyen, Gyuyoup Kim, Eung-Kwon Pae
Muscle fiber-type changes in hypoxic conditions in accordance with pyruvate dehydrogenase kinase (Pdk)-1 and hypoxia inducible factor (Hif)-1α were investigated in rats. Hif-1α and its down-stream molecule Pdk-1 are well known for readily response to hypoxia. We questioned their roles in relation to changes in myosin heavy chain (MyHC) composition in skeletal muscles. We hypothesize that the level of Pdk-1 with respect to the level of Hif-1α determines MyHC composition of the muscle in rats in hypoxia. Young male rats were housed in a chamber maintained at 11...
2016: Frontiers in Physiology
https://www.readbyqxmd.com/read/27876895/multiple-crosstalk-between-tor-and-the-cell-integrity-mapk-signaling-pathway-in-fission-yeast
#12
Marisa Madrid, Beatriz Vázquez-Marín, Alejandro Franco, Teresa Soto, Jero Vicente-Soler, Mariano Gacto, José Cansado
In eukaryotic cells, the highly conserved Target of Rapamycin (TOR) and the Mitogen Activated Protein Kinase (MAPK) signaling pathways elicit adaptive responses to extra- and intracellular conditions by regulating essential cellular functions. However, the nature of the functional relationships between both pathways is not fully understood. In the fission yeast Schizosaccharomyces pombe the cell integrity MAPK pathway (CIP) regulates morphogenesis, cell wall structure and ionic homeostasis. We show that the Rab GTPase Ryh1, a TORC2 complex activator, cross-activates the CIP and its core member, the MAPK Pmk1, by two distinct mechanisms...
November 23, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27874079/crosstalk-among-proteome-acetylome-and-succinylome-in-colon-cancer-hct116-cell-treated-with-sodium-dichloroacetate
#13
Danxi Zhu, Lidan Hou, Bin Hu, Hang Zhao, Jie Sun, Jianhua Wang, Xiangjun Meng
Protein lysine acetylation and succinylation play important regulatory roles in cells, both of which or each other has a close relationship. Dichloroacetate (DCA), a well-known pyruvate dehydrogenase kinase (PDK) inhibitor, has the potential to be used as anti-cancer drugs for several tumors including colorectal cancer. However, little is known about the potential mechanism of DCA-based cancer therapy by protein posttranslational modifications (PTM) including global proteome, acetylome and succinylome. Here the combinations with stable isotope labeling (SILAC), antibody affinity enrichment and high resolution LC-MS/MS analysis were performed in human colon cancer HCT116 cells...
November 22, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27856638/regulation-of-pyruvate-dehydrogenase-kinase-4-in-the-heart-through-degradation-by-the-lon-protease-in-response-to-mitochondrial-substrate-availability
#14
Clair Crewe, Christopher Schafer, Irene Lee, Michael Kinter, Luke I Szweda
Cardiac metabolic inflexibility is driven by robust up-regulation of pyruvate dehydrogenase kinase 4 (PDK4) and phosphorylation-dependent inhibition of pyruvate dehydrogenase (PDH) within a single day of feeding mice a high fat diet. In the current study, we have discovered that PDK4 is a short lived protein (t½ ∼ 1 h) and is specifically degraded by the mitochondrial protease Lon. Lon does not rapidly degrade PDK1 and -2, indicating specificity toward the PDK isoform that is a potent modulator of metabolic flexibility...
January 6, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27854075/benzimidazole-derivative-m084-extends-the-lifespan-of-caenorhabditis-elegans-in-a-daf-16-foxo-dependent-way
#15
Ai-Jun Ding, Gui-Sheng Wu, Bin Tang, Xuechuan Hong, Michael X Zhu, Huai-Rong Luo
With the growth of aging population, there is increasing demand to develop strategy to improve the aging process and aging-related diseases. Benzimidazole and its derivatives are crucial heterocyclic backbone of many drugs and compounds with diverse therapeutic applications, including alleviation of aging-related diseases. Here, we investigate if the benzimidazole derivative n-butyl-[1H]-benzimidazol-2-amine (M084), a novel inhibitor of TRPC4 and TRPC5 channels and antidepressant, could affect the lifespan of Caenorhabditis elegans (C...
February 2017: Molecular and Cellular Biochemistry
https://www.readbyqxmd.com/read/27795296/phd2-is-a-regulator-for-glycolytic-reprogramming-in-macrophages
#16
Annemarie Guentsch, Angelika Beneke, Lija Swain, Katja Farhat, Shunmugam Nagarajan, Ben Wielockx, Kaamini Raithatha, Jan Dudek, Peter Rehling, Anke Zieseniss, Aline Jatho, Mei Chong, Celio X C Santos, Ajay M Shah, Dörthe M Katschinski
The prolyl-4-hydroxylase domain (PHD) enzymes are regarded as the molecular oxygen sensors. There is an interplay between oxygen availability and cellular metabolism, which in turn has significant effects on the functionality of innate immune cells, such as macrophages. However, if and how PHD enzymes affect macrophage metabolism are enigmatic. We hypothesized that macrophage metabolism and function can be controlled via manipulation of PHD2. We characterized the metabolic phenotypes of PHD2-deficient RAW cells and primary PHD2 knockout bone marrow-derived macrophages (BMDM)...
January 1, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/27626688/diisopropylamine-dichloroacetate-enhances-radiosensitization-in-esophageal-squamous-cell-carcinoma-by-increasing-mitochondria-derived-reactive-oxygen-species-levels
#17
Gaochao Dong, Qiang Chen, Feng Jiang, Decai Yu, Qixing Mao, Wenjie Xia, Run Shi, Jie Wang, Lin Xu
Radiotherapy is generally applied in the treatment of esophageal squamous cell carcinoma (ESCC). However, the radioresistance of ESCC still remains an obstacle for the curative effect of this treatment. We hypothesized that diisopropylamine dichloroacetate (DADA), an inhibitor of pyruvate dehydrogenase kinase (PDK), might enhance radiosensitizationin resistant ESCC. The clonogenic survival assay revealed that DADA sensitized ESCC cells to radiotherapy in vitro; furthermore, the combination of DADA and radiotherapy increased the expression of γ-H2AX, which is a hallmark of DNA double-strand breaks...
October 18, 2016: Oncotarget
https://www.readbyqxmd.com/read/27626669/kdm4a-coactivates-e2f1-to-regulate-the-pdk-dependent-metabolic-switch-between-mitochondrial-oxidation-and-glycolysis
#18
Ling-Yu Wang, Chiu-Lien Hung, Yun-Ru Chen, Joy C Yang, Junjian Wang, Mel Campbell, Yoshihiro Izumiya, Hong-Wu Chen, Wen-Ching Wang, David K Ann, Hsing-Jien Kung
The histone lysine demethylase KDM4A/JMJD2A has been implicated in prostate carcinogenesis through its role in transcriptional regulation. Here, we describe KDM4A as a E2F1 coactivator and demonstrate a functional role for the E2F1-KDM4A complex in the control of tumor metabolism. KDM4A associates with E2F1 on target gene promoters and enhances E2F1 chromatin binding and transcriptional activity, thereby modulating the transcriptional profile essential for cancer cell proliferation and survival. The pyruvate dehydrogenase kinases (PDKs) PDK1 and PDK3 are direct targets of KDM4A and E2F1 and modulate the switch between glycolytic metabolism and mitochondrial oxidation...
September 13, 2016: Cell Reports
https://www.readbyqxmd.com/read/27605385/glucose-dependent-anaplerosis-in-cancer-cells-is-required-for-cellular-redox-balance-in-the-absence-of-glutamine
#19
Naniye Mallı Cetinbas, Jessica Sudderth, Robert C Harris, Aysun Cebeci, Gian L Negri, Ömer H Yılmaz, Ralph J DeBerardinis, Poul H Sorensen
Cancer cells have altered metabolism compared to normal cells, including dependence on glutamine (GLN) for survival, known as GLN addiction. However, some cancer cell lines do not require GLN for survival and the basis for this discrepancy is not well understood. GLN is a precursor for antioxidants such as glutathione (GSH) and NADPH, and GLN deprivation is therefore predicted to deplete antioxidants and increase reactive oxygen species (ROS). Using diverse human cancer cell lines we show that this occurs only in cells that rely on GLN for survival...
September 8, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27571309/reevaluation-of-two-quantitative-trait-loci-for-type-ii-resistance-to-fusarium-head-blight-in-wheat-germplasm-pi-672538
#20
X Li, Z P Xiang, W Q Chen, Q L Huang, T G Liu, Q Li, S F Zhong, M Zhang, J W Guo, L Lei, P G Luo
Fusarium head blight (FHB), mainly caused by Fusarium graminearum, is a destructive disease in wheat. A population consisting of 229 F2 and F2:3 plants derived from the cross PI 672538 × L661 was used to evaluate the reactions to FHB. The FHB resistance data distribution in the F2 population indicates that some quantitative trait loci (QTLs) were controlling the FHB resistance in PI 672538. We further detected two major QTLs (Qfhs-2B, Qfhs-3B) from analysis of the resistance data and the PCR-amplified results using WinQTLCart 2...
January 2017: Phytopathology
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