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Cancer AND glutamine

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https://www.readbyqxmd.com/read/29334372/pharmacological-blockade-of-asct2-dependent-glutamine-transport-leads-to-antitumor-efficacy-in-preclinical-models
#1
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...
January 15, 2018: Nature Medicine
https://www.readbyqxmd.com/read/29331336/udp-sugar-accumulation-drives-hyaluronan-synthesis-in-breast-cancer
#2
Sanna Oikari, Tiia Kettunen, Satu Tiainen, Jukka Häyrinen, Amro Masarwah, Mazen Sudah, Anna Sutela, Ritva Vanninen, Markku Tammi, Päivi Auvinen
Increased uptake of glucose, a general hallmark of malignant tumors, leads to an accumulation of intermediate metabolites of glycolysis. We investigated whether the high supply of these intermediates promotes their flow into UDP-sugars, and consequently into hyaluronan, a tumor-promoting matrix molecule. We quantified UDP-N-Acetylglucosamine (UDP-GlcNAc) and UDP-glucuronic acid (UDP-GlcUA) in human breast cancer biopsies, the levels of enzymes contributing to their synthesis, and their association with the hyaluronan accumulation in the tumor...
January 10, 2018: Matrix Biology: Journal of the International Society for Matrix Biology
https://www.readbyqxmd.com/read/29330792/evaluating-the-metabolic-impact-of-hypoxia-on-pancreatic-cancer-cells
#3
Divya Murthy, Enza Vernucci, Gennifer Goode, Jaime Abrego, Pankaj K Singh
Hypoxia is frequently observed in human cancers and induces global metabolic reprogramming that includes an increase in glucose uptake and glycolysis, alterations in NAD(P)H/NAD(P)+ and intracellular ATP levels, and increased utilization of glutamine as the major precursor for fatty acid synthesis. In this chapter, we describe in detail various physiological assays that have been adopted to study the metabolic shift propagated by exposure to hypoxic conditions in pancreatic cell culture model that includes glucose uptake, glutamine uptake, and lactate release by pancreatic cancer cell lines...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29326164/the-glutamine-transporter-asct2-slc1a5-promotes-tumor-growth-independently-of-the-amino-acid-transporter-lat1-slc7a5
#4
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 (EAA), 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 EAA 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...
January 11, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29324050/the-roles-of-adjuvant-supplements-in-colorectal-cancer-patients-on-chemotherapy-reaping-benefits-from-metabolic-crosstalk
#5
Babak Golkhalkhali, Audra Shaleena Paliany, Kin Fah Chin, Retnagowri Rajandram
The prevalence of colorectal cancer (CRC) is on a steady rise over the years, with the World Health Organization (WHO) reporting CRC as the fourth leading cause of cancer-related death worldwide. While treatment modalities may differ in accordance to the staging and severity of the disease itself, chemotherapy is almost unavoidable in most cases. Though effective in its mode of action, chemotherapy is commonly associated with undesirable side effects that negatively affects the patient in terms of quality of life, and in some cases may actually interfere with their treatment regimens, thus escalating to poor prognosis...
January 11, 2018: Nutrition and Cancer
https://www.readbyqxmd.com/read/29323154/effects-of-metformin-on-colorectal-cancer-stem-cells-depend-on-alterations-in-glutamine-metabolism
#6
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/29321164/kras-oncoprotein-expression-is-regulated-by-a-self-governing-eif5a-peak1-feed-forward-regulatory-loop
#7
Ken Fujimura, Huawei Wang, Felicia Watson, Richard L Klemke
There remains intense interest in tractable approaches to target or silence the KRAS oncoprotein as a rational therapeutic strategy to attack pancreatic adenocarcinoma (PDAC) and other cancers which overexpress it. Here we provide evidence that accumulation of the KRAS oncoprotein is controlled by a self-regulating feed-forward regulatory loop that utilizes a unique hypusinated isoform of the translation elongation factor eIF5A and the tyrosine kinase PEAK1. Oncogenic activation of KRAS increased eIF5A-PEAK1 translational signaling, which in turn facilitated increased KRAS protein synthesis...
January 10, 2018: Cancer Research
https://www.readbyqxmd.com/read/29317493/characterization-of-the-interactions-of-potent-allosteric-inhibitors-with-glutaminase-c-a-key-enzyme-in-cancer-cell-glutamine-metabolism
#8
Qingqiu Huang, Clint Stalnecker, Chengliang Zhang, Lee A McDermott, Prema Iyer, Jason O'Neill, Shawn Reimer, Richard A Cerione, William P Katt
Altered glycolytic flux in cancer cells (the Warburg effect) causes their proliferation to rely upon elevated glutamine metabolism (glutamine addiction). This requirement is met by the overexpression of glutaminase C (GAC), which catalyzes the first step in glutamine metabolism and therefore represents a potential therapeutic target. The small molecule CB-839 was reported to be more potent than other allosteric GAC inhibitors, including the parent compound BPTES, and is in clinical trials. Recently, we described the synthesis of BPTES analogs having distinct saturated heterocyclic cores as a replacement for the flexible chain moiety, with improved microsomal stability relative to CB-839 and BPTES...
January 9, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29299135/acquired-resistance-to-pi3k-mtor-inhibition-is-associated-with-mitochondrial-dna-mutation-and-glycolysis
#9
King Xin Koh, Gim Hwa Tan, Sarah Hong Hui Low, Mohd Feroz Mohd Omar, Min Ji Han, Barry Iacopetta, Ross Soo, Mounia Beloueche-Babari, Bhaskar Bhattacharya, Richie Soong
Acquired resistance (AQR) to drug treatment occurs frequently in cancer patients and remains an impediment to successful therapy. The aim of this study was to gain insight into how AQR arises following the application of PI3K/mTOR inhibitors. H1975 lung cancer cells with EGFR T790M mutations that confer resistance to EGFR inhibitors underwent prolonged treatment with the PI3K/mTOR inhibitor, BEZ235. Monoclonal cells with stable and increased resistance to BEZ235 were obtained after 8 months treatment. These AQR clones showed class-specific resistance to PI3K/mTOR inhibitors, reduced G1 cell cycle arrest and impedance of migration following PI3K/mTOR inhibition, reduced PTEN expression and increased Akt and S6RP phosphorylation...
December 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/29295993/structural-characterisation-reveals-insights-into-substrate-recognition-by-the-glutamine-transporter-asct2-slc1a5
#10
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/29290982/glucose-6-phosphate-dehydrogenase-and-transketolase-modulate-breast-cancer-cell-metabolic-reprogramming-and-correlate-with-poor-patient-outcome
#11
Adrián Benito, Ibrahim H Polat, Véronique Noé, Carlos J Ciudad, Silvia Marin, Marta Cascante
The pentose phosphate pathway is a fundamental metabolic pathway that provides cells with ribose and NADPH required for anabolic reactions - synthesis of nucleotides and fatty acids - and maintenance of intracellular redox homeostasis. It plays a key role in tumor metabolic reprogramming and has been reported to be deregulated in different types of tumors. Herein, we silenced the most important enzymes of this pathway - glucose-6-phosphate dehydrogenase (G6PD) and transketolase (TKT) - in the human breast cancer cell line MCF7...
December 5, 2017: Oncotarget
https://www.readbyqxmd.com/read/29258187/usefulness-of-amino-acid-profiling-in-ovarian-cancer-screening-with-special-emphasis-on-their-role-in-cancerogenesis
#12
Szymon Plewa, Agnieszka Horała, Paweł Dereziński, Agnieszka Klupczynska, Ewa Nowak-Markwitz, Jan Matysiak, Zenon J Kokot
The aim of this study was to quantitate 42 serum-free amino acids, propose the biochemical explanation of their role in tumor development, and identify new ovarian cancer (OC) biomarkers for potential use in OC screening. The additional value of this work is the schematic presentation of the interrelationship between metabolites which were identified as significant for OC development and progression. The liquid chromatography-tandem mass spectrometry technique using highly-selective multiple reaction monitoring mode and labeled internal standards for each analyzed compound was applied...
December 16, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29245936/podocalyxin-promotes-proliferation-and-survival-in-mature-b-cell-non-hodgkin-lymphoma-cells
#13
Estíbaliz Tamayo-Orbegozo, Laura Amo, Marta Riñón, Naiara Nieto, Elena Amutio, Natalia Maruri, Miren Solaun, Arantza Arrieta, Susana Larrucea
Podocalyxin (PCLP1) is a CD34-related sialomucin expressed by some normal cells and a variety of malignant tumors, including leukemia, and associated with the most aggressive cancers and poor clinical outcome. PCLP1 increases breast tumor growth, migration and invasion; however, its role in hematologic malignancies still remains undetermined. The purpose of this study was to investigate the expression and function of PCLP1 in mature B-cell lymphoma cells. We found that overexpression of PCLP1 significantly increases proliferation, cell-to-cell interaction, clonogenicity, and migration of B-cell lymphoma cells...
November 21, 2017: Oncotarget
https://www.readbyqxmd.com/read/29226720/memantine-induces-apoptosis-and-inhibits-cell-cycle-progression-in-lncap-prostate-cancer-cells
#14
G Albayrak, E Konac, A U Dikmen, C Y Bilen
Deregulated cancer cell metabolism plays an important role in cancer progression. Cancer cell metabolism has been in the centre of attention in therapeutical cancer cell targeting. Repurposed chemical agents, such as metformin and aspirin, have been studied extensively as preventive and therapeutic agents. Metformin is Food and Drug administration (FDA)-approved antidiabetic drug cheaper than other chemotherapeutic agents that were shown to have anticancer effects. Memantine is an FDA-approved Alzheimer's drug...
January 1, 2017: Human & Experimental Toxicology
https://www.readbyqxmd.com/read/29221133/endogenous-glutamine-decrease-is-associated-with-pancreatic-cancer-progression
#15
Cecilia Roux, Chiara Riganti, Sammy Ferri Borgogno, Roberta Curto, Claudia Curcio, Valeria Catanzaro, Giuseppe Digilio, Sergio Padovan, Maria Paola Puccinelli, Monica Isabello, Silvio Aime, Paola Cappello, Francesco Novelli
Pancreatic ductal adenocarcinoma (PDAC) is becoming the second leading cause of cancer-related death in the Western world. The mortality is very high, which emphasizes the need to identify biomarkers for early detection. As glutamine metabolism alteration is a feature of PDAC, its in vivo evaluation may provide a useful tool for biomarker identification. Our aim was to identify a handy method to evaluate blood glutamine consumption in mouse models of PDAC. We quantified the in vitro glutamine uptake by Mass Spectrometry (MS) in tumor cell supernatants and showed that it was higher in PDAC compared to non-PDAC tumor and pancreatic control human cells...
November 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/29217764/radiotherapy-activated-cancer-associated-fibroblasts-promote-tumor-progression-through-paracrine-igf-1r-activation
#16
Joke Tommelein, Elly De Vlieghere, Laurine Verset, Elodie Melsens, Justine Leenders, Benedicte Descamps, Annelies Debucquoy, Christian Vanhove, Patrick Pauwels, Christian P Gespach, Anne Vral, Astrid De Boeck, Karin Haustermans, Pascal de Tullio, Wim Ceelen, Pieter Demetter, Tom Boterberg, Marc Bracke, Olivier De Wever
Preoperative radiotherapy (RT) is a mainstay in the management of rectal cancer (RC), a tumor characterized by desmoplastic stroma containing cancer-associated fibroblasts (CAF). Although CAF are abundantly present, the effects of RT to CAF and its impact on cancer cells are unknown. We evaluated the damage responses of CAF to RT and investigated changes in colorectal cancer (CRC) cell growth, transcriptome, metabolome, and kinome in response to paracrine signals emerging from irradiated CAF. RT to CAF induced DNA damage, p53 activation, cell cycle arrest, and secretion of paracrine mediators including insulin-like growth factor-1 (IGF-1)...
December 7, 2017: Cancer Research
https://www.readbyqxmd.com/read/29212306/oncogene-driven-metabolic-alterations-in-cancer
#17
REVIEW
Hye-Young Min, Ho-Young Lee
Cancer is the leading cause of human deaths worldwide. Understanding the biology underlying the evolution of cancer is important for reducing the economic and social burden of cancer. In addition to genetic aberrations, recent studies demonstrate metabolic rewiring, such as aerobic glycolysis, glutamine dependency, accumulation of intermediates of glycolysis, and upregulation of lipid and amino acid synthesis, in several types of cancer to support their high demands on nutrients for building blocks and energy production...
December 7, 2017: Biomolecules & Therapeutics
https://www.readbyqxmd.com/read/29212303/targeting-glutamine-metabolism-for-cancer-treatment
#18
REVIEW
Yeon-Kyung Choi, Keun-Gyu Park
Rapidly proliferating cancer cells require energy and cellular building blocks for their growth and ability to maintain redox balance. Many studies have focused on understanding how cancer cells adapt their nutrient metabolism to meet the high demand of anabolism required for proliferation and maintaining redox balance. Glutamine, the most abundant amino acid in plasma, is a well-known nutrient used by cancer cells to increase proliferation as well as survival under metabolic stress conditions. In this review, we provide an overview of the role of glutamine metabolism in cancer cell survival and growth and highlight the mechanisms by which glutamine metabolism affects cancer cell signaling...
December 7, 2017: Biomolecules & Therapeutics
https://www.readbyqxmd.com/read/29212209/targeted-inhibition-of-glutaminase-as-a-potential-new-approach-for-the-treatment-of-nf1-associated-soft-tissue-malignancies
#19
Tahir N Sheikh, Parag P Patwardhan, Serge Cremers, Gary K Schwartz
Many cancer cells rely on glutamine as the source of carbon molecules to feed the biosynthetic pathways and are often addicted to glutaminolysis. Inhibitors of glutaminase activity have gained attention in the last few years due to their anti-proliferative effect and ability to induce apoptosis in some cancers. Although it is a promising therapeutic approach, its efficacy or the role played by glutamine in modulating cell proliferation in NF1 associated tumors has never been studied. We report for the first time, a strong correlation between the NF1 status of tumor cells and increased sensitivity to glutamine deprivation and glutaminase inhibition...
November 7, 2017: Oncotarget
https://www.readbyqxmd.com/read/29208682/the-receptor-tyrosine-kinase-epha2-promotes-glutamine-metabolism-in-tumors-by-activating-the-transcriptional-coactivators-yap-and-taz
#20
Deanna N Edwards, Verra M Ngwa, Shan Wang, Eileen Shiuan, Dana M Brantley-Sieders, Laura C Kim, Albert B Reynolds, Jin Chen
Malignant tumors reprogram cellular metabolism to support cancer cell proliferation and survival. Although most cancers depend on a high rate of aerobic glycolysis, many cancer cells also display addiction to glutamine. Glutamine transporters and glutaminase activity are critical for glutamine metabolism in tumor cells. We found that the receptor tyrosine kinase EphA2 activated the TEAD family transcriptional coactivators YAP and TAZ (YAP/TAZ), likely in a ligand-independent manner, to promote glutamine metabolism in cells and mouse models of HER2-positive breast cancer...
December 5, 2017: Science Signaling
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