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ASCT2

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https://www.readbyqxmd.com/read/29563155/sorting-nexin-27-snx27-regulates-the-trafficking-and-activity-of-the-glutamine-transporter-asct2
#1
Zhe Yang, Jordan Follett, Markus C Kerr, Thomas Clairfeuille, Mintu Chandra, Brett M Collins, Rohan D Teasdale
The Alanine, Serine, Cysteine-preferring Transporter 2 (ASCT2; SLC1A5) is responsible for the uptake of glutamine into cells, a major source of cellular energy and a key regulator of mammalian Target of Rapamycin (mTOR) activation. Furthermore, ASCT2 expression has reported in several human cancers making it a potential target for both diagnostic and therapeutic purposes. Here we identify ASCT2 as a membrane trafficked cargo molecule, sorted through a direct interaction with the PDZ domain of Sorting Nexin 27 (SNX27)...
March 21, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29495336/cys-site-directed-mutagenesis-of-the-human-slc1a5-asct2-transporter-structure-function-relationships-and-crucial-role-of-cys467-for-redox-sensing-and-glutamine-transport
#2
Mariafrancesca Scalise, Lorena Pochini, Lara Console, Gilda Pappacoda, Piero Pingitore, Kristina Hedfalk, Cesare Indiveri
The human plasma membrane transporter ASCT2 is responsible for mediating Na- dependent antiport of neutral amino acids. New insights into structure/function relationships were unveiled by a combined approach of recombinant over-expression, site-directed mutagenesis, transport assays in proteoliposomes and bioinformatics. WT and Cys mutants of hASCT2 were produced in P. pastoris and purified for functional assay. The reactivity towards SH reducing and oxidizing agents of WT protein was investigated and opposite effects were revealed; transport activity increased upon treatment with the Cys reducing agent DTE, i...
February 25, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29453360/role-of-intestinal-trefoil-factor-in-protecting-intestinal-epithelial-cells-from-burn-induced-injury
#3
Jianhong Hu, Yan Shi, Chao Wang, Hanxing Wan, Dan Wu, Hongyu Wang, Xi Peng
Although intestinal trefoil factor (ITF) can alleviate the burn-induced intestinal mucosa injury, the underlying mechanisms remains elusive. In this study, we investigated if ITF alters glutamine transport on the brush border membrane vesicles (BBMVs) of the intestines in Sprague-Dawley rats inflicted with 30% TBSA and the underlying mechanisms. We found that ITF significantly stimulated intestinal glutamine transport in burned rats. Mechanistically, ITF enhanced autophagy, reduces endoplasmic reticulum stress (ERS), and alleviates the impaired PDI, ASCT2, and B0AT1 in IECs and BBMVs after burn injury likely through AMPK activation...
February 16, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29435734/targeting-of-glutamine-transporter-asct2-and-glutamine-synthetase-suppresses-gastric-cancer-cell-growth
#4
Jianxin Ye, Qiang Huang, Jie Xu, Jinsheng Huang, Jinzhou Wang, Wenjing Zhong, Wannan Chen, Xinjian Lin, Xu Lin
PURPOSE: Glutamine (Gln) is essential for the proliferation of most cancer cells, making it an appealing target for cancer therapy. However, the role of Gln in gastric cancer (GC) metabolism is unknown and Gln-targeted therapy against GC remains scarce. The aim of this study was to investigate the relevance of Gln in GC growth and targeting. METHODS: Expression of Gln transporter ASCT2 and glutamine synthetase (GS) in the parental and molecularly engineered GC cells or in human GC specimens was determined by RT-PCR and western blot analysis or immunohistochemistry...
February 12, 2018: Journal of Cancer Research and Clinical Oncology
https://www.readbyqxmd.com/read/29363149/prolonged-survival-after-second-autologous-transplantation-and-lenalidomide-maintenance-for-salvage-treatment-of-myeloma-patients-at-first-relapse-after-prior-autograft
#5
Ursina Gössi, Barbara Jeker, Behrouz Mansouri Taleghani, Ulrike Bacher, Urban Novak, Daniel Betticher, Thomas Egger, Thilo Zander, Thomas Pabst
Autologous stem cell transplantation (ASCT) as part of the primary therapy in multiple myeloma (MM) is standard practice. In contrast, the role of a second ASCT (ASCT2) and subsequent lenalidomide maintenance for relapsed disease remains unclear. In this study, we analysed 86 consecutive MM patients with a first relapse after prior ASCT receiving either a second ASCT or conventional chemotherapy. After a median follow-up of 37.7 months since first relapse, 54 (62.8%) patients were still alive and 29 (33.7%) without progression...
January 24, 2018: Hematological Oncology
https://www.readbyqxmd.com/read/29334372/pharmacological-blockade-of-asct2-dependent-glutamine-transport-leads-to-antitumor-efficacy-in-preclinical-models
#6
Michael L Schulte, Allie Fu, Ping Zhao, Jun Li, Ling Geng, Shannon T Smith, Jumpei Kondo, Robert J Coffey, Marc O Johnson, Jeffrey C Rathmell, Joe T Sharick, Melissa C Skala, Jarrod A Smith, Jordan Berlin, M Kay Washington, Michael L Nickels, H Charles Manning
The unique metabolic demands of cancer cells underscore potentially fruitful opportunities for drug discovery in the era of precision medicine. However, therapeutic targeting of cancer metabolism has led to surprisingly few new drugs to date. The neutral amino acid glutamine serves as a key intermediate in numerous metabolic processes leveraged by cancer cells, including biosynthesis, cell signaling, and oxidative protection. Herein we report the preclinical development of V-9302, a competitive small molecule antagonist of transmembrane glutamine flux that selectively and potently targets the amino acid transporter ASCT2...
February 2018: Nature Medicine
https://www.readbyqxmd.com/read/29326164/the-glutamine-transporter-asct2-slc1a5-promotes-tumor-growth-independently-of-the-amino-acid-transporter-lat1-slc7a5
#7
Yann Cormerais, Pierre André Massard, Milica Vucetic, Sandy Giuliano, Eric Tambutté, Jerome Durivault, Valérie Vial, Hitoshi Endou, Michael F Wempe, Scott K Parks, Jacques Pouyssegur
The transporters for glutamine and essential amino acids, ASCT2 (solute carrier family 1 member 5, SLC1A5) and LAT1 (solute carrier family 7 member 5, SLC7A5), respectively, are overexpressed in aggressive cancers and have been identified as cancer-promoting targets. Moreover, previous work has suggested that glutamine influx via ASCT2 triggers essential amino acids entry via the LAT1 exchanger, thus activating mechanistic target of rapamycin complex 1 (mTORC1) and stimulating growth. Here, to further investigate whether these two transporters are functionally coupled, we compared the respective knockout (KO) of either LAT1 or ASCT2 in colon (LS174T) and lung (A549) adenocarcinoma cell lines...
February 23, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29323154/effects-of-metformin-on-colorectal-cancer-stem-cells-depend-on-alterations-in-glutamine-metabolism
#8
Jae Hyun Kim, Kyoung Jin Lee, Yoojeong Seo, Ji-Hee Kwon, Jae Pil Yoon, Jo Yeon Kang, Hyun Jung Lee, Soo Jung Park, Sung Pil Hong, Jae Hee Cheon, Won Ho Kim, Tae Ii Kim
Metformin has been known to suppress cancer stem cells (CSCs) in some cancers. However, the differential effects of metformin on CSCs and their mechanisms have not been reported. Herein, metformin induced pAMPK activation and pS6 suppression in metformin-sensitive (HT29) cells, but not in metformin-resistant (SW620) cells. The oxygen consumption rate was higher in HT29 cells than in SW620 cells and showed a prominent decrease after metformin treatment in HT29 cells. In glutamine-depleted medium, but not in low-glucose medium, SW620 cells became sensitive to the CSC-suppressing effect of metformin...
January 11, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29295993/structural-characterisation-reveals-insights-into-substrate-recognition-by-the-glutamine-transporter-asct2-slc1a5
#9
Amanda J Scopelliti, Josep Font, Robert J Vandenberg, Olga Boudker, Renae M Ryan
Cancer cells undergo a shift in metabolism where they become reliant on nutrients such as the amino-acid glutamine. Glutamine enters the cell via the alanine/serine/cysteine transporter 2 (ASCT2) that is upregulated in several cancers to maintain an increased supply of this nutrient and are therefore an attractive target in cancer therapeutic development. ASCT2 belongs to the glutamate transporter (SLC1A) family but is the only transporter in this family able to transport glutamine. The structural basis for glutamine selectivity of ASCT2 is unknown...
January 2, 2018: Nature Communications
https://www.readbyqxmd.com/read/29221178/cytotoxic-stress-induces-transfer-of-mitochondria-associated-human-endogenous-retroviral-rna-and-proteins-between-cancer-cells
#10
David Díaz-Carballo, Jacqueline Klein, Ali H Acikelli, Camilla Wilk, Sahitya Saka, Holger Jastrow, Gunther Wennemuth, Phillip Dammann, Urs Giger-Pabst, Veria Khosrawipour, Joachim Rassow, Mikalai Nienen, Dirk Strumberg
About 8 % of the human genome consists of human endogenous retroviruses (HERVs), which are relicts of ancient exogenous retroviral infections incurred during evolution. Although the majority of HERVs have functional gene defects or epigenetic modifications, many of them are still able to produce retroviral proteins that have been proposed to be involved in cellular transformation and cancer development. We found that, in chemo-resistant U87RETO glioblastoma cells, cytotoxic stress induced by etoposide promotes accumulation and large-scale fission of mitochondria, associated with the detection of HERV-WE1 (syncytin-1) and HERV-FRD1 (syncytin-2) in these organelles...
November 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/29202102/combinatorial-treatment-with-natural-compounds-in-prostate-cancer-inhibits-prostate-tumor-growth-and-leads-to-key-modulations-of-cancer-cell-metabolism
#11
Alessia Lodi, Achinto Saha, Xiyuan Lu, Bo Wang, Enrique Sentandreu, Meghan Collins, Mikhail G Kolonin, John DiGiovanni, Stefano Tiziani
High-throughput screening of a natural compound library was performed to identify the most efficacious combinatorial treatment on prostate cancer. Ursolic acid, curcumin and resveratrol were selected for further analyses and administered in vivo via the diet, either alone or in combination, in a mouse allograft model of prostate cancer. All possible combinations of these natural compounds produced synergistic effects on tumor size and weight, as predicted in the screens. A subsequent untargeted metabolomics and metabolic flux analysis using isotopically labeled glutamine indicated that the compound combinations modulated glutamine metabolism...
2017: NPJ Precision Oncology
https://www.readbyqxmd.com/read/29151270/asc-amino-acid-transporter-2-defined-by-enzyme-mediated-activation-of-radical-sources-enhances-malignancy-of-gd2-positive-small-cell-lung-cancer
#12
Nobutoshi Esaki, Yuki Ohkawa, Noboru Hashimoto, Yuhsuke Tsuda, Yuhsuke Ohmi, Robiul H Bhuiyan, Norihiro Kotani, Koichi Honke, Atsushi Enomoto, Masahide Takahashi, Keiko Furukawa, Koichi Furukawa
Ganglioside GD2 is specifically expressed in small-cell lung cancer (SCLC) cells, leading to enhancement of malignant phenotypes, such as cell proliferation and migration. However, how GD2 promotes malignant phenotypes in SCLC cells is not well known. In this study, to reveal the mechanisms by which GD2 increases malignant phenotypes in SCLC cells, we used enzyme-mediated activation of radical sources combined with mass spectrometry in GD2+ SCLC cells. Consequently, we identified ASC amino acid transporter 2 (ASCT2), a major glutamine transporter, which coordinately works with GD2...
January 2018: Cancer Science
https://www.readbyqxmd.com/read/29020998/proteomic-profiling-of-breast-cancer-metabolism-identifies-shmt2-and-asct2-as-prognostic-factors
#13
Stephan Bernhardt, Michaela Bayerlová, Martina Vetter, Astrid Wachter, Devina Mitra, Volker Hanf, Tilmann Lantzsch, Christoph Uleer, Susanne Peschel, Jutta John, Jörg Buchmann, Edith Weigert, Karl-Friedrich Bürrig, Christoph Thomssen, Ulrike Korf, Tim Beissbarth, Stefan Wiemann, Eva Johanna Kantelhardt
BACKGROUND: Breast cancer tumors are known to be highly heterogeneous and differences in their metabolic phenotypes, especially at protein level, are less well-understood. Profiling of metabolism-related proteins harbors the potential to establish new patient stratification regimes and biomarkers promoting individualized therapy. In our study, we aimed to examine the relationship between metabolism-associated protein expression profiles and clinicopathological characteristics in a large cohort of breast cancer patients...
October 11, 2017: Breast Cancer Research: BCR
https://www.readbyqxmd.com/read/28885889/a-genetic-variant-of-asct2-hampers-in-vitro-rna-splicing-and-correlates-with-human-longevity
#14
Patrizia D'Aquila, Paolina Crocco, Francesco De Rango, Cesare Indiveri, Dina Bellizzi, Giuseppina Rose, Giuseppe Passarino
Given the role of amino acid regulation for physiological and pathological cell proliferation, we investigated whether the variability of solute carrier family 1, member 5 (SLC1A5, namely ASCT2), encoding for ASCT2 protein, a major glutamine transporter, is related to longevity. A total of 607 differently aged unrelated individuals, 351 very old subjects (≥85 years, range 85-106 years, mean age 93.82 ± 4.44 years) and 256 younger controls (<85 years, range 64-84 years, mean age 73.60 ± 5.70 years) were analyzed...
September 8, 2017: Rejuvenation Research
https://www.readbyqxmd.com/read/28807674/phenylglycine-analogs-are-inhibitors-of-the-neutral-amino-acid-transporters-asct1-and-asct2-and-enhance-nmda-receptor-mediated-ltp-in-rat-visual-cortex-slices
#15
Alan C Foster, Natalie Rangel-Diaz, Ursula Staubli, Jia-Ying Yang, Mahmud Penjwini, Veena Viswanath, Yong-Xin Li
The N-methyl-d-aspartate receptor (NMDA) co-agonist d-serine is a substrate for the neutral amino acid transporters ASCT1 (SLC1A4) and ASCT2 (SLC1A5). We identified l-phenylglycine (PG) and its analogs as inhibitors of ASCT1 and ASCT2. PG analogs were shown to be non-substrate inhibitors of ASCT1 and ASCT2 with a range of activities relative to other amino acid transport systems, including sodium-dependent glutamate transporters, the sodium-independent d-serine transporter asc-1 and system L. L-4-chloroPG was the most potent and selective ASCT1/2 inhibitor identified...
August 12, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28804556/anti-tumor-efficacy-evaluation-of-a-novel-monoclonal-antibody-targeting-neutral-amino-acid-transporter-asct2-using-patient-derived-xenograft-mouse-models-of-gastric-cancer
#16
Noriyuki Kasai, Aya Sasakawa, Kenta Hosomi, Tze Wei Poh, Bernadette Lynn Chua, Wei Peng Yong, Jimmy So, Shing Leng Chan, Richie Soong, Koji Kono, Toshihiko Ishii, Kazuya Yamano
ASC amino acid transporter 2 (ASCT2), also known as solute linked carrier family 1 member A5 (SLC1A5) is a Na+-dependent glutamine/neutral amino acid transporter. ASCT2 acts as a high-affinity transporter of L-glutamine (Gln) and has been reported to be up-regulated in a variety of cancerous tissues including stomach, liver, and kidney. In this study, we evaluated anti-tumor efficacy of a novel anti-ASCT2 humanized monoclonal antibody, KM8094, which has a neutralizing activity against glutamine uptake, as a therapeutic antibody against gastric cancer and explored clinical predictive biomarker candidates by utilizing patient-derived xenograft (PDX) mouse models...
2017: American Journal of Translational Research
https://www.readbyqxmd.com/read/28759021/asct2-regulates-glutamine-uptake-and-cell-growth-in-endometrial-carcinoma
#17
A D Marshall, M van Geldermalsen, N J Otte, T Lum, M Vellozzi, A Thoeng, A Pang, R Nagarajah, B Zhang, Q Wang, L Anderson, J E J Rasko, J Holst
Glutamine commonly becomes a conditionally essential amino acid in cancer. Glutamine is supplied to the cell by transporters such as ASCT2 (SLC1A5), which is frequently upregulated in multiple cancers. Here we investigated the expression of ASCT2 in endometrial carcinoma, and evaluated the contribution of ASCT2 to glutamine uptake and endometrial cancer cell growth. Analysis of human gene expression data showed that ASCT2 was significantly upregulated in both endometrioid and serous subtypes of endometrial carcinoma, compared to normal, age-matched endometrium...
July 31, 2017: Oncogenesis
https://www.readbyqxmd.com/read/28749408/clinical-role-of-asct2-slc1a5-in-kras-mutated-colorectal-cancer
#18
Kosuke Toda, Gen Nishikawa, Masayoshi Iwamoto, Yoshiro Itatani, Ryo Takahashi, Yoshiharu Sakai, Kenji Kawada
Mutation in the KRAS gene induces prominent metabolic changes. We have recently reported that KRAS mutations in colorectal cancer (CRC) cause alterations in amino acid metabolism. However, it remains to be investigated which amino acid transporter can be regulated by mutated KRAS in CRC. Here, we performed a screening of amino acid transporters using quantitative reverse-transcription polymerase chain reaction (RT-PCR) and then identified that ASCT2 (SLC1A5) was up-regulated through KRAS signaling. Next, immunohistochemical analysis of 93 primary CRC specimens revealed that there was a significant correlation between KRAS mutational status and ASCT2 expression...
July 27, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28729677/engineering-tumour-cell-binding-synthetic-polymers-with-sensing-dense-transporters-associated-with-aberrant-glutamine-metabolism
#19
Naoki Yamada, Yuto Honda, Hiroyasu Takemoto, Takahiro Nomoto, Makoto Matsui, Keishiro Tomoda, Masamitsu Konno, Hideshi Ishii, Masaki Mori, Nobuhiro Nishiyama
Increased glutamine uptake toward the elevated glutaminolysis is one of the hallmarks of tumour cells. This aberrant glutamine metabolism has recently attracted considerable attention as a diagnostic and therapeutic target. Herein, we developed glutamine-functionalized polymer to achieve a selective high affinity to tumour cells overexpressing glutaminolysis-related transporter ASCT2. In in vitro study, our developed polymer exhibited faster and higher cellular uptake in tumour cells than that in normal cells...
July 20, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28692032/epigenetic-silencing-of-microrna-137-enhances-asct2-expression-and-tumor-glutamine-metabolism
#20
J Dong, D Xiao, Z Zhao, P Ren, C Li, Y Hu, J Shi, H Su, L Wang, H Liu, B Li, P Gao, G Qing
Tumor cells must activate specific transporters to meet their increased glutamine metabolic demands. Relative to other glutamine transporters, the ASC family transporter 2 (ASCT2, also called SLC1A5) is profoundly elevated in a wide spectrum of human cancers to coordinate metabolic reprogramming and malignant transformation. Understanding the molecular mechanisms whereby tumor cells frequently upregulate this transporter is therefore vital to develop potential strategies for transporter-targeted therapies. Combining in-silico algorithms with systemic experimental screening, we herein identify the tumor suppressor microRNA, miR-137, as an essential regulator that targets ASCT2 and cancer cell glutamine metabolism...
July 10, 2017: Oncogenesis
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