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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...
September 8, 2016: Oncotarget
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
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...
2016: Scientific Reports
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...
October 18, 2016: Phytopathology
S R Mishra, M S Parmar, V P Yadav, R Reshma, J Bharati, M K Bharti, A Paul, V S Chouhan, G Taru Sharma, G Singh, M Sarkar
The objective of this study was to document the expression and localization of angiopoietin (ANGPT) family members comprising of angiopoietin (ANGPT1 and ANGPT2), and their receptors (Tie1 and Tie2) in buffalo corpus luteum (CL) obtained from different stages of the oestrous cycle, and the modulatory role of ANGPT1 and ANGPT2 alone or in combinations on progesterone (P4 ) secretion and mRNA expression of phosphotidylinositide-3kinase-protein kinase B (PI3K-AKT), phosphoinositide-dependent kinase (PDK), protein kinase B (AKT), Bcl2 associated death promoter (BAD), caspase 3 and von willebrand factor (vWF) in luteal cells obtained from midluteal phase (MLP) of oestrous cycle in buffalo...
August 28, 2016: Reproduction in Domestic Animals, Zuchthygiene
Zheng Yang, Kin Y Tam
Glycolysis has been observed as a predominant process for most cancer cells to utilize glucose, which was referred to as "Warburg Effect". Targeting critical enzymes, such as pyruvate dehydrogenase kinase (PDK) that inversely regulating the process of glycolysis could be a promising approach to work alone or in combination with other treatments for cancer therapy. EGFR inhibitors for Non-Small-Cell Lung Cancer (NSCLC) treatment have been applied for decades in clinical practices with great success, but also their clinical benefits were somewhat hampered by the rising acquired-resistance...
October 15, 2016: European Journal of Pharmacology
Gwon-Soo Jung, Jae-Han Jeon, Yeon-Kyung Choi, Se Young Jang, Soo Young Park, Sung-Woo Kim, Jun-Kyu Byun, Mi-Kyung Kim, Sungwoo Lee, Eui-Cheol Shin, In-Kyu Lee, Yu Na Kang, Keun-Gyu Park
During replication, hepatitis C virus (HCV) utilizes macromolecules produced by its host cell. This process requires host cellular metabolic reprogramming to favor elevated levels of aerobic glycolysis. Therefore, we evaluated whether pyruvate dehydrogenase kinase (PDK), a mitochondrial enzyme that promotes aerobic glycolysis, can regulate HCV replication. Levels of c-Myc, hypoxia-inducible factor-1α (HIF-1α), PDK1, PDK3, glucokinase, and serine biosynthetic enzymes were compared between HCV-infected and uninfected human liver and Huh-7...
2016: Scientific Reports
Seiko Yoshino, Toshiro Hara, Hiroki J Nakaoka, Akane Kanamori, Yoshinori Murakami, Motoharu Seiki, Takeharu Sakamoto
Loss of anchorage to the extracellular matrix leads to apoptosis (anoikis) in normal cells, but cancerous cells are usually resistant to such stress. Here we report the pivotal role of an E3 ubiquitin ligase, ring-finger protein 126 (RNF126), in the resistance of cancer cells to the stress associated with non-adherent conditions. Non-adherent cancer cells exhibited increased flux through the tricarboxylic acid cycle via increased conversion of pyruvate to acetyl-CoA. RNF126 was found to act as a ubiquitin ligase for pyruvate dehydrogenase kinases (PDKs), resulting in their proteasomal degradation...
2016: Cell Discovery
Tiziana Masini, Barbara Birkaya, Simon van Dijk, Milon Mondal, Johan Hekelaar, Manuel Jäger, Anke C Terwisscha van Scheltinga, Mulchand S Patel, Anna K H Hirsch, Edelmiro Moman
The last decade has witnessed the reawakening of cancer metabolism as a therapeutic target. In particular, inhibition of pyruvate dehydrogenase kinase (PDK) holds remarkable promise. Dichloroacetic acid (DCA), currently undergoing clinical trials, is a unique PDK inhibitor in which it binds to the allosteric pyruvate site of the enzyme. However, the safety of DCA as a drug is compromised by its neurotoxicity, whereas its usefulness as an investigative tool is limited by the high concentrations required to exert observable effects in cell culture...
July 19, 2016: Journal of Enzyme Inhibition and Medicinal Chemistry
Justine I Blum, Kaiser M Bijli, Tamara C Murphy, Jennifer M Kleinhenz, C Michael Hart
BACKGROUND: Pathogenesis of pulmonary hypertension is complex and involves activation of the transcription factor, hypoxia-inducible factor-1 (HIF-1) that shifts cellular metabolism from aerobic respiration to glycolysis, in part, by increasing the expression of its downstream target pyruvate dehydrogenase kinase-1 (PDK-1), thereby promoting a proliferative, apoptosis-resistant phenotype in pulmonary vascular cells. Activation of the nuclear hormone transcription factor, peroxisome proliferator-activated receptor gamma (PPARγ), attenuates pulmonary hypertension and pulmonary artery smooth muscle cell (PASMC) proliferation...
July 2016: American Journal of the Medical Sciences
Gonzalo Perez-Siles, Carolyn Ly, Adrienne Grant, Alexander P Drew, Eppie M Yiu, Monique M Ryan, David T Chuang, Shih-Chia Tso, Garth A Nicholson, Marina L Kennerson
Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral neuropathy. An X-linked form of CMT (CMTX6) is caused by a missense mutation (R158H) in the pyruvate dehydrogenase kinase isoenzyme 3 (PDK3) gene. PDK3 is one of 4 isoenzymes that negatively regulate the activity of the pyruvate dehydrogenase complex (PDC) by reversible phosphorylation of its first catalytic component pyruvate dehydrogenase (designated as E1). Mitochondrial PDC catalyses the oxidative decarboxylation of pyruvate to acetyl CoA and links glycolysis to the energy-producing Krebs cycle...
October 2016: Neurobiology of Disease
Shan-Qing Zheng, Xiao-Bing Huang, Ti-Kun Xing, Ai-Jun Ding, Gui-Sheng Wu, Huai-Rong Luo
Coffee and tea, two of the most popular drinks around the world, share many in common from chemical components to beneficial effects on human health. One of their shared components, the polyphenols, most notably chlorogenic acid (CGA), was supposed to account for many of the beneficial effects on ameliorating diseases occurred accompanying people aging, such as the antioxidant effect and against diabetes and cardiovascular disease. CGA is also present in many traditional Chinese medicines. However, the mechanism of these effects was vague...
July 4, 2016: Journals of Gerontology. Series A, Biological Sciences and Medical Sciences
Stephen L Archer
There is no cure for non-small-cell lung cancer (NSCLC) or pulmonary arterial hypertension (PAH). Therapies lack efficacy and/or are toxic, reflecting a failure to target disease abnormalities that are distinct from processes vital to normal cells. NSCLC and PAH share reversible mitochondrial-metabolic abnormalities which may offer selective therapeutic targets. The following mutually reinforcing, mitochondrial abnormalities favor proliferation, impair apoptosis, and are relatively restricted to PAH and cancer cells: (1) Epigenetic silencing of superoxide dismutase-2 (SOD2) by methylation of CpG islands creates a pseudohypoxic redox environment that causes normoxic activation of hypoxia inducible factor (HIF-1α)...
2016: Advances in Experimental Medicine and Biology
Tao Gao, Jian Chen, Zhiqi Shi
Pyruvate dehydrogenase kinase (PDK) is an important mitochondrial enzyme that blocks the production of acetyl-CoA by selectively inhibiting the activity of pyruvate dehydrogenase (PDH) through phosphorylation. PDK is an effectively therapeutic target in cancer cells, but the physiological roles of PDK in phytopathogens are largely unknown. To address these gaps, a PDK gene (FgPDK1) was isolated from Fusarium graminearum that is an economically important pathogen infecting cereals. The deletion of FgPDK1 in F...
2016: PloS One
Santosh K Misra, Mao Ye, Fatemeh Ostadhossein, Dipanjan Pan
Anticancer agents based on haloacetic acids are developed for inhibition of pyruvate dehydrogenase kinase (PDK), an enzyme responsible for reversing the suppression of mitochondria-dependent apoptosis. Through molecular docking studies mono- and dihaloacetates are identified as potent PDK2 binders and matched their efficiency with dichloroacetic acid. In silico screening directed their conversion to phospholipid prodrugs, which were subsequently self-assembled to pro-haloacetate nanoparticles. Following a thorough physico-chemical characterization, the functional activity of these novel agents was established in wide ranges of human cancer cell lines in vitro and in vivo in rodents...
2016: Scientific Reports
Zhi-Cheng Jing, Rui Zhang
The survival of patients with pulmonary arterial hypertension is closely related with right ventricular function. During the progression of right ventricular remodeling, the energetic metabolism shifts from oxidative mitochondrial metabolism to the glycolysis. In normal physiological conditions, cardiomyocytes used major sources of glucose and fatty acids to sustain a continuous systolic workload and energy supply. The property allowed the heart to choose the most efficient substrate to response to environmental stimuli...
June 13, 2016: Current Pharmaceutical Design
S Drozdovska, B Gavenauskas, T Drevytska, V Nosar, V Nagibin, I Mankovska, V Dosenko
Molecular mechanisms of adaptation to exercise despite a large number of studies remain unclear. One of the crucial factors in this process is hypoxia inducible factor (HIF) that regulates transcription of many target genes encoding proteins that are implicated in molecular adaptation to hypoxia. Experiments were conducted on 24 adult male Fisher rats. Real-time PCR analysis was performed for quantitative evaluation of Hif3α, Igf1, Glut-4 and Pdk-1 in m. gastrocnemius, m. soleus, in lung and heart tissues...
June 2016: Biology of Sport
Tian Gao, Zeng-Yan Zhu, Xiang Zhou, Mei-Lin Xie
CONTEXT: Chrysanthemum morifolium Ramat. (Asteraceae) extract (CME) possesses a vasodilator effect in vitro. However, the use of polyphenol-rich CME in the treatment of hypertension-induced cardiac hypertrophy has not been reported. OBJECTIVE: We investigated the effect of polyphenol-rich CME on hypertension-induced cardiac hypertrophy in rats and its possible mechanism of action. MATERIALS AND METHODS: The Sprague-Dawley rat model with cardiac hypertrophy was induced by renovascular hypertension...
June 7, 2016: Pharmaceutical Biology
Anthony S Malamas, Erlei Jin, Maneesh Gujrati, Zheng-Rong Lu
Stabilization of hypoxia inducible factor 1α (HIF-1α), a biomarker of hypoxia, in hypoxic tumors mediates a variety of downstream genes promoting tumor angiogenesis and cancer cell survival as well as invasion, and compromising therapeutic outcome. In this study, dynamic contrast enhanced MRI (DCE-MRI) with a biodegradable macromolecular MRI contrast agent was used to noninvasively assess the antiangiogenic effect of RGD-targeted multifunctional lipid ECO/siHIF-1α nanoparticles in a mouse HT29 colon cancer model...
July 5, 2016: Molecular Pharmaceutics
Nir Qvit, Marie-Hélène Disatnik, Eiketsu Sho, Daria Mochly-Rosen
Protein kinases regulate numerous cellular processes, including cell growth, metabolism, and cell death. Because the primary sequence and the three-dimensional structure of many kinases are highly similar, the development of selective inhibitors for only one kinase is challenging. Furthermore, many protein kinases are pleiotropic, mediating diverse and sometimes even opposing functions by phosphorylating multiple protein substrates. Here, we set out to develop an inhibitor of a selective protein kinase phosphorylation of only one of its substrates...
June 22, 2016: Journal of the American Chemical Society
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