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https://www.readbyqxmd.com/read/28230853/mesenchymal-stromal-cells-inhibit-cd25-expression-via-the-mtor-pathway-to-potentiate-t-cell-suppression
#1
Hyun Seung Yoo, Kyuheon Lee, Kwangmin Na, Yong Xu Zhang, Hyun-Ja Lim, TacGhee Yi, Sun U Song, Myung-Shin Jeon
Mesenchymal stromal cells (MSCs) are known to suppress T-cell activation and proliferation. Several studies have reported that MSCs suppress CD25 expression in T cells. However, the molecular mechanism underlying MSC-mediated suppression of CD25 expression has not been fully examined. Here, we investigated the mTOR pathway, which is involved in CD25 expression in T cells. We showed that MSCs inhibited CD25 expression, which was restored in the presence of an inducible nitric oxide synthase (iNOS) inhibitor...
February 23, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28220896/mitochondrial-dysregulation-secondary-to-endoplasmic-reticulum-stress-in-autosomal-dominant-tubulointerstitial-kidney-disease-umod-adtkd-umod
#2
Elisabeth Kemter, Thomas Fröhlich, Georg J Arnold, Eckhard Wolf, Rüdiger Wanke
'Autosomal dominant tubulointerstitial kidney disease - UMOD' (ADTKD-UMOD) is caused by impaired maturation and secretion of mutant uromodulin (UMOD) in thick ascending limb of Henle loop (TAL) cells, resulting in endoplasmic reticulum (ER) stress and unfolded protein response (UPR). To gain insight into pathophysiology, we analysed proteome profiles of TAL-enriched outer renal medulla samples from ADTKD-UMOD and control mice by quantitative LC-MS/MS. In total, 212 differentially abundant proteins were identified...
February 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28192515/salmonella-typhimurium-disrupts-sirt1-ampk-checkpoint-control-of-mtor-to-impair-autophagy
#3
Raja Ganesan, Nina Judith Hos, Saray Gutierrez, Julia Fischer, Joanna Magdalena Stepek, Evmorphia Daglidu, Martin Krönke, Nirmal Robinson
During intracellular infections, autophagy significantly contributes to the elimination of pathogens, regulation of pro-inflammatory signaling, secretion of immune mediators and in coordinating the adaptive immune system. Intracellular pathogens such as S. Typhimurium have evolved mechanisms to circumvent autophagy. However, the regulatory mechanisms targeted by S. Typhimurium to modulate autophagy have not been fully resolved. Here we report that cytosolic energy loss during S. Typhimurium infection triggers transient activation of AMPK, an important checkpoint of mTOR activity and autophagy...
February 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28185117/a-lesson-from-a-reported-pathogenic-variant-in-peutz-jeghers-syndrome-a-case-report
#4
Hu Tan, Xianda Wei, Pu Yang, Yanru Huang, Haoxian Li, Desheng Liang, Lingqian Wu
Peutz-Jeghers syndrome (PJS) is a rare autosomal dominant disorder characterized by mucocutaneous hyperpigmentation, gastrointestinal (GI) hamartmatous polyps, and an increased risk of various malignancies. Pathogenic variants in the LKB1 tumor suppressor gene (also known as STK11) are the major cause of PJS. In this study, compound heterozygous variants of LKB1, c.890G > A/ c.1062C > G and del(exon1)/ c.1062C > G, were identified in two sporadic Chinese PJS cases respectively. Although all these three variants had been related to the autosomal dominant PJS in previous studies, all evidences collected in this study including de novo data, segregation data, population data, in-silico data, and functional data indicated that del(exon1) and c...
February 9, 2017: Familial Cancer
https://www.readbyqxmd.com/read/28184053/gastrointestinal-diseases-and-their-oro-dental-manifestations-part-4-peutz-jeghers-syndrome
#5
S E Korsse, M E van Leerdam, E Dekker
Peutz-Jeghers syndrome (PJS) is a rare, autosomal dominant inherited disorder, caused by germline mutations in the LKB1 tumour suppressor gene. It is clinically characterised by distinct perioral mucocutaneous pigmentations, gastrointestinal polyposis and an increased cancer risk in adult life. Hamartomatous polyps can develop already in the first decade of life and may cause various complications, including abdominal pain, bleeding, anaemia, and acute intestinal obstruction. Furthermore, patients have an increased risk for developing cancer, both in the gastrointestinal tract as in other organs...
February 10, 2017: British Dental Journal
https://www.readbyqxmd.com/read/28177708/the-effect-of-caffeine-on-skeletal-muscle-anabolic-signaling-and-hypertrophy
#6
Timothy M Moore, Xavier M Mortensen, Conrad K Ashby, Alexander M Harris, Karson J Kump, David W Laird, Aaron J Adams, Jeremy K Bray, Ting Chen, David M Thomson
Caffeine is a widely-consumed stimulant with the potential to enhance physical performance through multiple mechanisms. However, recent in vitro findings have suggested that caffeine may block skeletal muscle anabolic signaling through AMP-activated protein kinase (AMPK)-mediated inhibition of mechanistic target of rapamycin (mTOR) signaling pathway. This could negatively affect protein synthesis and the capacity for muscle growth. The primary purpose of this study was to assess the effect of caffeine on in vivo AMPK and mTOR pathway signaling, protein synthesis and muscle growth...
January 26, 2017: Applied Physiology, Nutrition, and Metabolism, Physiologie Appliquée, Nutrition et Métabolisme
https://www.readbyqxmd.com/read/28147319/mevastatin-blockade-of-autolysosome-maturation-stimulates-lbh589-induced-cell-death-in-triple-negative-breast-cancer-cells
#7
Zhaohu Lin, Zhuqing Zhang, Xiaoxiao Jiang, Xinhui Kou, Yong Bao, Huijuan Liu, Fanghui Sun, Shuang Ling, Ning Qin, Lan Jiang, Yonghua Yang
Histone deacetylase inhibitors (HDACi) are promising anti-cancer agents, and combining a HDACi with other agents is an attractive therapeutic strategy in solid tumors. We report here that mevastatin increases HDACi LBH589-induced cell death in triple-negative breast cancer (TNBC) cells. Combination treatment inhibited autophagic flux by preventing Vps34/Beclin 1 complex formation and downregulating prenylated Rab7, an active form of the small GTPase necessary for autophagosome-lysosome fusion. This means that co-treatment with mevastatin and LBH589 activated LKB1/AMPK signaling and subsequently inhibited mTOR...
January 27, 2017: Oncotarget
https://www.readbyqxmd.com/read/28123944/celastrol-ameliorates-liver-metabolic-damage-caused-by-a-high-fat-diet-through-sirt1
#8
Yinliang Zhang, Chao Geng, Xiaoyan Liu, Meixia Li, Mingyue Gao, Xiaojun Liu, Fude Fang, Yongsheng Chang
OBJECTIVE: Celastrol was recently identified as a potential novel treatment for obesity. However, the effect of Celastrol on nonalcoholic fatty liver disease (NAFLD) remains elusive. The aim of this study is to evaluate the role of Celastrol in NAFLD. METHODS: Functional studies were performed using wild-type C57BL/6J (WT) mice and liver specific Sirt1-deficient (LKO) mice. The molecular mechanism was explored in primary mouse liver and primary hepatocytes. RESULTS: When WT mice receiving a high-fat diet (HFD) were treated with Celastrol, reductions in body weight, subcutaneous and visceral fat content, and liver lipid droplet formation were observed, along with reduced hepatic intracellular triglyceride and serum triglyceride, free fatty acid, and ALT concentrations...
January 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/28119362/lkb1-expression-correlates-with-increased-survival-in-advanced-non-small-cell-lung-cancer-patients-treated-with-chemotherapy-and-bevacizumab
#9
Laura Bonanno, Angela De Paoli, Elisabetta Zulato, Giovanni Esposito, Fiorella Calabrese, Adolfo Favaretto, Antonio Santo, Alessandro Del Conte, Marco Chilosi, Francesco Oniga, Gabriella Sozzi, Massimo Moro, Francesco Ciccarese, Giorgia Nardo, Roberta Bertorelle, Cinzia Candiotto, Gian Luca De Salvo, Alberto Amadori, PierFranco Conte, Stefano Indraccolo
PURPOSE: LKB1 is a key sensor of metabolic stress, including hypoxia and glucose deprivation, two features of the tumor microenvironment exacerbated by antiangiogenic therapy. We investigated the role of LKB1 as potential predictive marker of sensitivity to bevacizumab in advanced non-small cell lung cancer (aNSCLC). EXPERIMENTAL DESIGN: We retrospectively analyzed LKB1 expression by immunohistochemistry in 98 samples out of 125 aNSCLC patients, including 59 patients treated with chemotherapy (CT) and 39 treated with CT plus bevacizumab...
January 24, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28102310/coordinated-cell-motility-is-regulated-by-a-combination-of-lkb1-farnesylation-and-kinase-activity
#10
S Wilkinson, Y Hou, J T Zoine, J Saltz, C Zhang, Z Chen, L A D Cooper, A I Marcus
Cell motility requires the precise coordination of cell polarization, lamellipodia formation, adhesion, and force generation. LKB1 is a multi-functional serine/threonine kinase that associates with actin at the cellular leading edge of motile cells and suppresses FAK. We sought to understand how LKB1 coordinates these multiple events by systematically dissecting LKB1 protein domain function in combination with live cell imaging and computational approaches. We show that LKB1-actin colocalization is dependent upon LKB1 farnesylation leading to RhoA-ROCK-mediated stress fiber formation, but membrane dynamics is reliant on LKB1 kinase activity...
January 19, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28099846/cell-of-origin-links-histotype-spectrum-to-immune-microenvironment-diversity-in-non-small-cell-lung-cancer-driven-by-mutant-kras-and-loss-of-lkb1
#11
Ashwini S Nagaraj, Jenni Lahtela, Annabrita Hemmes, Teijo Pellinen, Sami Blom, Jennifer R Devlin, Kaisa Salmenkivi, Olli Kallioniemi, Mikko I Mäyränpää, Katja Närhi, Emmy W Verschuren
Lung cancers exhibit pronounced functional heterogeneity, confounding precision medicine. We studied how the cell of origin contributes to phenotypic heterogeneity following conditional expression of Kras(G12D) and loss of Lkb1 (Kras;Lkb1). Using progenitor cell-type-restricted adenoviral Cre to target cells expressing surfactant protein C (SPC) or club cell antigen 10 (CC10), we show that Ad5-CC10-Cre-infected mice exhibit a shorter latency compared with Ad5-SPC-Cre cohorts. We further demonstrate that CC10(+) cells are the predominant progenitors of adenosquamous carcinoma (ASC) tumors and give rise to a wider spectrum of histotypes that includes mucinous and acinar adenocarcinomas...
January 17, 2017: Cell Reports
https://www.readbyqxmd.com/read/28087886/d-chiro-inositol-ameliorates-endothelial-dysfunction-via-inhibition-of-oxidative-stress-and-mitochondrial-fission
#12
Bobo Zhang, Xudan Guo, Yunlong Li, Qiang Peng, Jinfeng Gao, Baolin Liu, Min Wang
SCOPE: D-chiro inositol (DCI), an isomer of inositol, possesses anti-oxidative and endothelial protective properties. The mechanism by which DCI prevents endothelial dysfunction was investigated, with emphasis on oxidative stress. METHODS AND RESULTS: DCI was found to inhibit NOX4 induction and enhance Nrf2 activity in palmitate (PA)-stimulated cells, showing that DCI prevents oxidative stress. DCI suppressed Ser616 phosphorylation and increased Ser637 phosphorylation of Drp1 and inhibited PA-induced mitochondrial fission...
January 14, 2017: Molecular Nutrition & Food Research
https://www.readbyqxmd.com/read/28087810/akt1-lkb1-and-yap1-revealed-as-myc-interactors-with-nanoluc-based-protein-fragment-complementation-assay
#13
Xiulei Mo, Qi Qi, Andrei A Ivanov, Qiankun Niu, Yin Luo, Jonathan Havel, Russell Goetze, Sydney Bell, Carlos S Moreno, Lee A D Cooper, Margaret A Johns, Fadlo R Khuri, Yuhong Du, Haian Fu
The c-Myc (MYC) transcription factor is a major cancer driver and a well-validated therapeutic target. However, directly targeting MYC has been challenging. Thus, identifying proteins that interact with and regulate MYC may provide alternative strategies to inhibit its oncogenic activity. In this study, we report the development of a NanoLuc-based protein-fragment complementation assay (NanoPCA) and mapping of the MYC protein interaction hub in live mammalian cells. The NanoPCA system was configured to enable detection of protein-protein interactions (PPI) at the endogenous level, as shown with PRAS40 dimerization, and detection of weak interactions, such as PINCH1-NCK2...
April 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28071670/benzyl-isothiocyanate-potentiates-p53-signaling-and-antitumor-effects-against-breast-cancer-through-activation-of-p53-lkb1-and-p73-lkb1-axes
#14
Bei Xie, Arumugam Nagalingam, Panjamurthy Kuppusamy, Nethaji Muniraj, Peter Langford, Balázs Győrffy, Neeraj K Saxena, Dipali Sharma
Functional reactivation of p53 pathway, although arduous, can potentially provide a broad-based strategy for cancer therapy owing to frequent p53 inactivation in human cancer. Using a phosphoprotein-screening array, we found that Benzyl Isothiocynate, (BITC) increases p53 phosphorylation in breast cancer cells and reveal an important role of ERK and PRAS40/MDM2 in BITC-mediated p53 activation. We show that BITC rescues and activates p53-signaling network and inhibits growth of p53-mutant cells. Mechanistically, BITC induces p73 expression in p53-mutant cells, disrupts the interaction of p73 and mutant-p53, thereby releasing p73 from sequestration and allowing it to be transcriptionally active...
January 10, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28069811/tgf-%C3%AE-1-smad3-pathway-targets-pp2a-ampk-foxo1-signaling-to-regulate-hepatic-gluconeogenesis
#15
Hariom Yadav, Samir Devalaraja, Stephanie T Chung, Sushil G Rane
Maintenance of glucose homeostasis is essential for normal physiology. Deviation from normal glucose levels, in either direction, increases susceptibility to serious medical complications such as hypoglycemia and diabetes. Maintenance of glucose homeostasis is achieved via functional interactions among various organs: liver, skeletal muscle, adipose tissue, brain, and the endocrine pancreas. The liver is the primary site of endogenous glucose production, especially during states of prolonged fasting. However, enhanced gluconeogenesis is also a signature feature of type 2 diabetes (T2D)...
February 24, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28067405/lkb1-regulation-of-skeletal-muscle-development-metabolism-and-muscle-progenitor-cell-homeostasis
#16
REVIEW
Tizhong Shan, Ziye Xu, Jiaqi Liu, Weiche Wu, Yizhen Wang
Liver kinase B1 (Lkb1), also named as Serine/Threonine protein kinase 11 (STK11), is a serine/threonine kinase that plays crucial roles in various cellular processes including cell survival, cell division, cellular polarity, cell growth, cell differentiation, and cell metabolism. In metabolic tissues, Lkb1 regulates glucose homeostasis and energy metabolism through phosphorylating and activating the AMPK subfamily proteins. In skeletal muscle, Lkb1 affects muscle development and postnatal growth, lipid and fatty acid oxidation, glucose metabolism and insulin sensitivity...
January 9, 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/28045069/local-alignment-vectors-reveal-cancer-cell-induced-ecm-fiber-remodeling-dynamics
#17
Byoungkoo Lee, Jessica Konen, Scott Wilkinson, Adam I Marcus, Yi Jiang
Invasive cancer cells interact with the surrounding extracellular matrix (ECM), remodeling ECM fiber network structure by condensing, degrading, and aligning these fibers. We developed a novel local alignment vector analysis method to quantitatively measure collagen fiber alignment as a vector field using Circular Statistics. This method was applied to human non-small cell lung carcinoma (NSCLC) cell lines, embedded as spheroids in a collagen gel. Collagen remodeling was monitored using second harmonic generation imaging under normal conditions and when the LKB1-MARK1 pathway was disrupted through RNAi-based approaches...
January 3, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28034896/role-of-cps1-in-cell-growth-metabolism-and-prognosis-in-lkb1-inactivated-lung-adenocarcinoma
#18
Müge Çeliktaş, Ichidai Tanaka, Satyendra Chandra Tripathi, Johannes F Fahrmann, Clemente Aguilar-Bonavides, Pamela Villalobos, Oliver Delgado, Dilsher Dhillon, Jennifer B Dennison, Edwin J Ostrin, Hong Wang, Carmen Behrens, Kim-Anh Do, Adi F Gazdar, Samir M Hanash, Ayumu Taguchi
BACKGROUND: Liver kinase B1 (LKB1) is a tumor suppressor in lung adenocarcinoma (LADC). We investigated the proteomic profiles of 45 LADC cell lines with and without LKB1 inactivation. Carbamoyl phosphate synthetase 1 (CPS1), the first rate-limiting mitochondrial enzyme in the urea cycle, was distinctively overexpressed in LKB1-inactivated LADC cell lines. We therefore assessed the role of CPS1 and its clinical relevance in LKB1-inactivated LADC. METHODS: Mass spectrometric profiling of proteome and metabolome and function of CPS1 were analyzed in LADC cell lines...
March 2017: Journal of the National Cancer Institute
https://www.readbyqxmd.com/read/28034771/lkb1-promotes-metabolic-flexibility-in-response-to-energy-stress
#19
Seth J Parker, Robert U Svensson, Ajit S Divakaruni, Austin E Lefebvre, Anne N Murphy, Reuben J Shaw, Christian M Metallo
The Liver Kinase B1 (LKB1) tumor suppressor acts as a metabolic energy sensor to regulate AMP-activated protein kinase (AMPK) signaling and is commonly mutated in various cancers, including non-small cell lung cancer (NSCLC). Tumor cells deficient in LKB1 may be uniquely sensitized to metabolic stresses, which may offer a therapeutic window in oncology. To address this question we have explored how functional LKB1 impacts the metabolism of NSCLC cells using (13)C metabolic flux analysis. Isogenic NSCLC cells expressing functional LKB1 exhibited higher flux through oxidative mitochondrial pathways compared to those deficient in LKB1...
December 26, 2016: Metabolic Engineering
https://www.readbyqxmd.com/read/28031112/-overexpression-of-liver-kinase-b1-inhibits-the-proliferation-of-lung-cancer-cells
#20
Yang Li, Libin Zhang, Ping Wang
Objective To explore the effect of overexpressed liver kinase B1(LKB1) on the proliferation of lung cancer cell lines. Methods The expression levels of LKB1 and PTEN in A549, NCI-H23, NCI-H157, XWLC-05, NCI-H446 lung cancer cells were detected by immunocytochemistry (ICC) and Western blotting. Plasmid pcDNA3.1(+)-LKB1 and empty vector pcDNA3.1(+)-null were separately transfected into the above five cell lines, and then the expression of LKB1 mRNA and protein were determined by quantitative real-time PCR and Western blotting, respectively...
January 2017: Xi Bao Yu Fen Zi Mian Yi Xue za Zhi, Chinese Journal of Cellular and Molecular Immunology
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