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https://www.readbyqxmd.com/read/28648777/mtorc2-regulates-amino-acid-metabolism-in-cancer-by-phosphorylation-of-the-cystine-glutamate-antiporter-xct
#1
Yuchao Gu, Claudio P Albuquerque, Daniel Braas, Wei Zhang, Genaro R Villa, Junfeng Bi, Shiro Ikegami, Kenta Masui, Beatrice Gini, Huijun Yang, Timothy C Gahman, Andrew K Shiau, Timothy F Cloughesy, Heather R Christofk, Huilin Zhou, Kun-Liang Guan, Paul S Mischel
Mutations in cancer reprogram amino acid metabolism to drive tumor growth, but the molecular mechanisms are not well understood. Using an unbiased proteomic screen, we identified mTORC2 as a critical regulator of amino acid metabolism in cancer via phosphorylation of the cystine-glutamate antiporter xCT. mTORC2 phosphorylates serine 26 at the cytosolic N terminus of xCT, inhibiting its activity. Genetic inhibition of mTORC2, or pharmacologic inhibition of the mammalian target of rapamycin (mTOR) kinase, promotes glutamate secretion, cystine uptake, and incorporation into glutathione, linking growth factor receptor signaling with amino acid uptake and utilization...
June 22, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28639254/use-of-a-digital-phantom-developed-by-qiba-for-harmonizing-suvs-obtained-from-the-state-of-the-art-spect-ct-systems-a-multicenter-study
#2
Tadaki Nakahara, Hiromitsu Daisaki, Yasushi Yamamoto, Takashi Iimori, Kazuyuki Miyagawa, Tomoya Okamoto, Yoshiki Owaki, Nobuhiro Yada, Koichi Sawada, Ryotaro Tokorodani, Masahiro Jinzaki
BACKGROUND: Although quantitative analysis using standardized uptake value (SUV) becomes realistic in clinical single-photon emission computed tomography/computed tomography (SPECT/CT) imaging, reconstruction parameter settings can deliver different quantitative results among different SPECT/CT systems. This study aims to propose a use of the digital reference object (DRO), which is a National Electrical Manufacturers Association (NEMA) phantom-like object developed by the Quantitative Imaging Biomarker Alliance (QIBA) fluorodeoxyglucose-positron emission tomography technical committee, for the purpose of harmonizing SUVs in Tc-99m SPECT/CT imaging...
December 2017: EJNMMI Research
https://www.readbyqxmd.com/read/28630042/the-glutamate-cystine-antiporter-slc7a11-xct-enhances-cancer-cell-dependency-on-glucose-by-exporting-glutamate
#3
Pranavi Koppula, Yilei Zhang, Jiejun Shi, Wei Li, Boyi Gan
Cancer cells with specific genetic alterations may be highly dependent on certain nutrients for survival, which can inform therapeutic strategies to target these cancer-specific metabolic vulnerabilities. The glutamate/cystine antiporter solute carrier family 7 member 11 (SLC7A11, also called xCT) is overexpressed in several cancers. Contrasting the established pro-survival roles of SLC7A11 under other stress conditions, here we report an unexpected finding that SLC7A11 overexpression enhances cancer cell dependency on glucose and renders cancer cells more sensitive to glucose starvation-induced cell death, and conversely, that SLC7A11 deficiency by either knockdown or pharmacological inhibition promotes cancer cell survival upon glucose starvation...
June 19, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28624317/modulatory-effects-of-ampicillin-sulbactam-on-glial-glutamate-transporters-and-metabotropic-glutamate-receptor-1-as-well-as-reinstatement-to-cocaine-seeking-behavior
#4
Alaa M Hammad, Fawaz Alasmari, Yusuf S Althobaiti, Youssef Sari
Glutamatergic system has an important role in cocaine-seeking behavior. Studies have reported that chronic exposure to cocaine induces downregulation of glutamate transporter-1 (GLT-1) and cystine/glutamate exchanger (xCT) in the central reward brain regions. Ceftriaxone, a β-lactam antibiotic, restored GLT-1 expression and consequently reduced cue-induced reinstatement of cocaine-seeking behavior. In this study, we investigated the reinstatement to cocaine (20mg/kg, i.p.) seeking behavior using a conditioned place preference (CPP) paradigm in male alcohol-preferring (P) rats...
June 15, 2017: Behavioural Brain Research
https://www.readbyqxmd.com/read/28610554/slc7a11-over-expression-in-glioblastoma-is-associated-with-increased-cancer-stem-cell-like-properties
#5
Monika Dagmara Polewski, Rosyli Francis Reveron-Thornton, Gregory Allan Cherryholmes, Georgi K Marinov, Karen Saida Aboody
System xc- is a sodium independent electro-neutral transporter, composed of a catalytic subunit xCT (SLC7A11) which is involved in importing cystine. Certain cancers such as gliomas up-regulate the expression of system xc- which confers a survival advantage against the detrimental effects of reactive oxygen species (ROS) by increasing the generation of the antioxidant glutathione. However, ROS have also been shown to function as targeted, intracellular second messengers in an array of physiological processes such as proliferation...
June 13, 2017: Stem Cells and Development
https://www.readbyqxmd.com/read/28553953/atf4-promotes-angiogenesis-and-neuronal-cell-death-and-confers-ferroptosis-in-a-xct-dependent-manner
#6
D Chen, Z Fan, M Rauh, M Buchfelder, I Y Eyupoglu, N Savaskan
Activating transcription factor 4 (ATF4) is a critical mediator of metabolic and oxidative homeostasis and cell survival. ATF4 is elevated in response to diverse microenvironmental stresses, including starvation, ER stress damages and exposure to toxic factors. Here we show that ATF4 expression fosters the malignancy of primary brain tumors (WHO grade III and IV gliomas) and increases proliferation and tumor angiogenesis. Hence, ATF4 expression promotes cell migration and anchorage-independent cell growth, whereas siRNA-mediated knockdown of ATF4 attenuates these features of malignancy in human gliomas...
May 29, 2017: Oncogene
https://www.readbyqxmd.com/read/28540184/detection-of-intramyocardially-injected-dir-labeled-mesenchymal-stem-cells-by-optical-and-optoacoustic-tomography
#7
Markus T Berninger, Pouyan Mohajerani, Moritz Wildgruber, Nicolas Beziere, Melanie A Kimm, Xiaopeng Ma, Bernhard Haller, Megan J Fleming, Stephan Vogt, Martina Anton, Andreas B Imhoff, Vasilis Ntziachristos, Reinhard Meier, Tobias D Henning
The distribution of intramyocardially injected rabbit MSCs, labeled with the near-infrared dye 1,1'-dioctadecyl-3,3,3',3'-tetramethylindotricarbo-cyanine-iodide (DiR) using hybrid Fluorescence Molecular Tomography-X-ray Computed Tomography (FMT-XCT) and Multispectral Optoacoustic Tomography (MSOT) imaging technologies, was investigated. Viability and induction of apoptosis of DiR labeled MSCs were assessed by XTT- and Caspase-3/-7-testing in vitro. 2 × 10(6), 2 × 10(5) and 2 × 10(4) MSCs labeled with 5 and 10 μg DiR/ml were injected into fresh frozen rabbit hearts...
June 2017: Photoacoustics
https://www.readbyqxmd.com/read/28538211/the-oxido-metabolic-driver-atf4-enhances-temozolamide-chemo-resistance-in-human-gliomas
#8
Daishi Chen, Manfred Rauh, Michael Buchfelder, Ilker Y Eyupoglu, Nicolai Savaskan
Malignant gliomas are devastating neoplasia with limited curative treatment options. Temozolomide (TMZ, Temcat®, Temodal® or Temodar®) is a first-line treatment for malignant gliomas but the development of drug resistance remains a major concern. Activating transcription factor 4 (ATF4) is a critical oxido-metabolic regulator in gliomas, and its role in the pathogenesis of TMZ-resistance remains elusive. We investigated the effect of TMZ on human glioma cells under conditions of enhanced ATF4 expression (ATF4OE) and ATF4 knock down (ATF4KD)...
May 9, 2017: Oncotarget
https://www.readbyqxmd.com/read/28525376/exploiting-ros-and-metabolic-differences-to-kill-cisplatin-resistant-lung-cancer
#9
Medhi Wangpaichitr, Chunjing Wu, Ying Ying Li, Dan J M Nguyen, Hande Kandemir, Sumedh Shah, Shumei Chen, Lynn G Feun, Jeffrey S Prince, Macus T Kuo, Niramol Savaraj
Cisplatin resistance remains a major problem in the treatment of lung cancer. We have discovered that cisplatin resistant (CR) lung cancer cells, regardless of the signaling pathway status, share the common parameter which is an increase in reactive oxygen species (ROS) and undergo metabolic reprogramming. CR cells were no longer addicted to the glycolytic pathway, but rather relied on oxidative metabolism. They took up twice as much glutamine and were highly sensitive to glutamine deprivation. Glutamine is hydrolyzed to glutamate for glutathione synthesis, an essential factor to abrogate high ROS via xCT antiporter...
May 2, 2017: Oncotarget
https://www.readbyqxmd.com/read/28495973/contrasting-the-role-of-xct-and-glt-1-upregulation-in-the-ability-of-ceftriaxone-to-attenuate-the-cue-induced-reinstatement-of-cocaine-seeking-and-normalize-ampa-receptor-subunit-expression
#10
Amber L LaCrosse, Sinead M O'Donovan, Marian T Sepulveda-Orengo, Robert E McCullumsmith, Kathryn J Reissner, Marek Schwendt, Lori A Knackstedt
Long-term treatment with ceftriaxone attenuates the reinstatement of cocaine seeking while increasing the function of the glutamate transporter 1 (GLT-1) and system xC- (Sxc) in the nucleus accumbens core (NAc). Sxc contributes the majority of nonsynaptic extracellular glutamate in the NAc, while GLT-1 is responsible for the majority of glutamate uptake. Here we used antisense to decrease the expression of GLT-1 and xCT (a catalytic subunit of Sxc) to determine the relative importance of both proteins in mediating the ability of ceftriaxone to prevent cue-induced reinstatement of cocaine seeking and normalize glutamatergic proteins in the NAc of rats...
June 14, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28458574/identification-of-capsazepine-as-a-novel-inhibitor-of-system-xc-and-cancer-induced-bone-pain
#11
Jennifer Fazzari, Matthew D Balenko, Natalie Zacal, Gurmit Singh
The cystine/glutamate antiporter has been implicated in a variety of cancers as a major mediator of redox homeostasis. The excess glutamate secreted by this transporter in aggressive cancer cells has been associated with cancer-induced bone pain (CIBP) from distal breast cancer metastases. High-throughput screening of small molecule inhibitors of glutamate release from breast cancer cells identified several potential compounds. One such compound, capsazepine (CPZ), was confirmed to inhibit the functional unit of system xc(-) (xCT) through its ability to block uptake of its radiolabeled substrate, cystine...
2017: Journal of Pain Research
https://www.readbyqxmd.com/read/28457879/the-role-of-system-xc-in-methamphetamine-induced-dopaminergic-neurotoxicity-in-mice
#12
Duy-Khanh Dang, Eun-Joo Shin, Hai-Quyen Tran, Dae-Joong Kim, Ji Hoon Jeong, Choon-Gon Jang, Seung-Yeol Nah, Hideyo Sato, Toshitaka Nabeshima, Yukio Yoneda, Hyoung-Chun Kim
The cystine/glutamate antiporter (system Xc(-), Sxc) transports cystine into cell in exchange for glutamate. Since xCT is a specific subunit of Sxc, we employed xCT knockout mice and investigated whether this antiporter affected methamphetamine (MA)-induced dopaminergic neurotoxicity. MA treatment significantly increased striatal oxidative burdens in wild type mice. xCT inhibitor [i.e., S-4-carboxy-phenylglycine (CPG), sulfasalazine] or an xCT knockout significantly protected against these oxidative burdens...
April 27, 2017: Neurochemistry International
https://www.readbyqxmd.com/read/28442364/effects-of-repeated-cocaine-exposure-and-withdrawal-on-voluntary-ethanol-drinking-and-the-expression-of-glial-glutamate-transporters-in-mesocorticolimbic-system-of-p-rats
#13
Alaa M Hammad, Yusuf S Althobaiti, Sujan C Das, Youssef Sari
Glutamatergic neurotransmission within the brain's reward circuits plays a major role in the reinforcing properties of both ethanol and cocaine. Glutamate homeostasis is regulated by several glutamate transporters, including glutamate transporter type 1 (GLT-1), cystine/glutamate transporter (xCT), and glutamate aspartate transporter (GLAST). Cocaine exposure has been shown to induce a dysregulation in glutamate homeostasis and a decrease in the expression of GLT-1 and xCT in the nucleus accumbens (NAc). In this study, alcohol preferring (P) rats were exposed to free-choice of ethanol (15% and 30%) and/or water for five weeks...
April 22, 2017: Molecular and Cellular Neurosciences
https://www.readbyqxmd.com/read/28429737/the-glutamate-cystine-xct-antiporter-antagonizes-glutamine-metabolism-and-reduces-nutrient-flexibility
#14
Chun-Shik Shin, Prashant Mishra, Jeramie D Watrous, Valerio Carelli, Marilena D'Aurelio, Mohit Jain, David C Chan
As noted by Warburg, many cancer cells depend on the consumption of glucose. We performed a genetic screen to identify factors responsible for glucose addiction and recovered the two subunits of the xCT antiporter (system xc(-)), which plays an antioxidant role by exporting glutamate for cystine. Disruption of the xCT antiporter greatly improves cell viability after glucose withdrawal, because conservation of glutamate enables cells to maintain mitochondrial respiration. In some breast cancer cells, xCT antiporter expression is upregulated through the antioxidant transcription factor Nrf2 and contributes to their requirement for glucose as a carbon source...
April 21, 2017: Nature Communications
https://www.readbyqxmd.com/read/28420170/fisetin-protects-pc12-cells-from-tunicamycin-mediated-cell-death-via-reactive-oxygen-species-scavenging-and-modulation-of-nrf2-driven-gene-expression-sirt1-and-mapk-signaling-in-pc12-cells
#15
Jui-Hung Yen, Pei-Shan Wu, Shu-Fen Chen, Ming-Jiuan Wu
BACKGROUND: Fisetin (3,7,3',4'-tetrahydroxyflavone) is a dietary flavonol and exhibits antioxidant, anti-inflammatory, and neuroprotective activities. However, high concentration of fisetin is reported to produce reactive oxygen species (ROS), induce endoplasmic reticulum (ER) stress and cause cytotoxicity in cancer cells. The aim of this study is to investigate the cytoprotective effects of low concentration of fisetin against tunicamycin (Tm)-mediated cytotoxicity in neuronal-like catecholaminergic PC12 cells...
April 17, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28390315/glutathione-inhibits-antibody-and-complement-mediated-immunologic-cell-injury-via-multiple-mechanisms
#16
Zhen Zhang, Xiling Zhang, Xin Fang, Manabu Niimi, Yanru Huang, Honglan Piao, Shan Gao, Jianglin Fan, Jian Yao
Antioxidant glutathione (GSH) plays an important role in the regulation of immunity. However, little is known about its effects on humoral immunity, especially its action on effector molecules like antibody and complement. Given that these molecules contain abundant disulfide bonds, we speculated that GSH might influence the action of these proteins via its thiol function. Using a model of a glomerular mesangial cell (MC) lysis induced by antibodies plus complement, we addressed this hypothesis. Exposure of rat MCs to anti-Thy-1 antibody plus complement or anti-MC rabbit serum caused a complement-dependent cell lysis, which was completely blocked by GSH...
August 2017: Redox Biology
https://www.readbyqxmd.com/read/28384716/analysis-of-mthfr-cbs-glutathione-taurine-and-hydrogen-sulfide-levels-in-retinas-of-hyperhomocysteinemic-mice
#17
Xuezhi Cui, Soumya Navneet, Jing Wang, Penny Roon, Wei Chen, Ming Xian, Sylvia B Smith
Purpose: Hyperhomocysteinemia (Hhcy) is implicated in certain retinal neurovascular diseases, although whether it is causative remains uncertain. In isolated ganglion cells (GCs), mild Hhcy induces profound death, whereas retinal phenotypes in Hhcy mice caused by mutations in remethylation (methylene tetrahydrofolatereductase [Mthfr+/-]) or transsulfuration pathways (cystathionine β-synthase [Cbs+/-]) demonstrate mild GC loss and mild vasculopathy. The current work investigated compensation in vivo of one pathway for the other, and, because the transsulfuration pathway yields cysteine necessary for formation of glutathione (GSH), taurine, and hydrogen sulfide (H2S), they were analyzed also...
April 1, 2017: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/28381035/quasi-supercontinuum-source-in-the-extreme-ultraviolet-using-multiple-frequency-combs-from-high-harmonic-generation
#18
Martin Wünsche, Silvio Fuchs, Stefan Aull, Jan Nathanael, Max Möller, Christian Rödel, Gerhard G Paulus
A quasi-supercontinuum source in the extreme ultraviolet (XUV) is demonstrated using a table-top femtosecond laser and a tunable optical parametric amplifier (OPA) as a driver for high-harmonic generation (HHG). The harmonic radiation, which is usually a comb of odd multiples of the fundamental frequency, is generated by near-infrared (NIR) laser pulses from the OPA. A quasi-continuous XUV spectrum in the range of 30 to 100 eV is realized by averaging over multiple harmonic comb spectra with slightly different fundamental frequencies and thus different spectral spacing between the individual harmonics...
March 20, 2017: Optics Express
https://www.readbyqxmd.com/read/28347687/effects-of-chronic-inhalation-of-electronic-cigarettes-containing-nicotine-on-glial-glutamate-transporters-and-%C3%AE-7-nicotinic-acetylcholine-receptor-in-female-cd-1-mice
#19
Fawaz Alasmari, Laura E Crotty Alexander, Jessica A Nelson, Isaac T Schiefer, Ellen Breen, Christopher A Drummond, Youssef Sari
Alteration in glutamate neurotransmission has been found to mediate the development of drug dependence, including nicotine. We and others, through using western blotting, have reported that exposure to drugs of abuse reduced the expression of glutamate transporter-1 (GLT-1) as well as cystine/glutamate antiporter (xCT), which consequently increased extracellular glutamate concentrations in the mesocorticolimbic area. However, our previous studies did not reveal any changes in glutamate/aspartate transporter (GLAST) following exposure to drugs of abuse...
July 3, 2017: Progress in Neuro-psychopharmacology & Biological Psychiatry
https://www.readbyqxmd.com/read/28345346/thermally-activated-delayed-fluorescence-and-aggregation-induced-emission-with-through-space-charge-transfer
#20
Hiroyuki Tsujimoto, Dong-Gwang Ha, Georgios Markopoulos, Hyun Sik Chae, Marc A Baldo, Timothy M Swager
Emissive molecules comprising a donor and an acceptor bridged by 9,9-dimethylxanthene, were studied (XPT, XCT, and XtBuCT). The structures position the donor and acceptor with cofacial alignment at distances of 3.3-3.5 Å wherein efficient spatial charge transfer can occur. The quantum yields were enhanced by excluding molecular oxygen and thermally activated delayed fluorescence with lifetimes on the order of microseconds was observed. Although the molecules displayed low quantum yields in solution, higher quantum yields were observed in the solid state...
March 27, 2017: Journal of the American Chemical Society
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