Abstract：
BACKGROUND AND PURPOSE:Pancreatic cancer is a solid tumour that is often fatal. Hence, there is an urgent need to identify new drug targets for this disease. Highly proliferating cancer cells have an increased demand for nutrients and, therefore, need to up-regulate selective amino acid transporters. Here, we investigated which amino acid transporters are up-regulated in pancreatic cancer and whether any of these transporters has potential as a drug target for this fatal disease. EXPERIMENTAL APPROACH:The expression of amino acid transporters in pancreatic cancer was analysed using publicly available microarray datasets, and the findings with the transporter SLC6A14 were validated by mRNA and protein analysis. The potential of SLC6A14 as a drug target was evaluated using a pharmacological blocker in vitro and in vivo. KEY RESULTS:SLC6A14 was up-regulated several fold in patient-derived xenografts, primary tumour tissues and pancreatic cancer cells lines compared to normal pancreatic tissue or normal pancreatic epithelial cells. The magnitude of the up-regulation of SLC6A14 was the highest among the amino acid transporters examined. A pharmacological blocker of SLC6A14, α-methyltryptophan, induced amino acid starvation in pancreatic cancer cells and reduced the growth and proliferation of these cells, both in vitro and in vivo. CONCLUSION AND IMPLICATIONS:The salient features of this study are that SLC6A14 is markedly up-regulated in pancreatic cancer and that pharmacological blockade of this transporter interferes with amino acid nutrition and reduces growth and proliferation of pancreatic cancer cells. These findings identify SLC6A14 as a novel druggable target for pancreatic cancer.
journal_name
Br J Pharmacoljournal_title
British journal of pharmacologyauthors
Coothankandaswamy V,Cao S,Xu Y,Prasad PD,Singh PK,Reynolds CP,Yang S,Ogura J,Ganapathy V,Bhutia YDdoi
10.1111/bph.13616subject
Has Abstractpub_date
2016-12-01 00:00:00pages
3292-3306issue
23eissn
0007-1188issn
1476-5381journal_volume
173pub_type
杂志文章abstract：BACKGROUND AND PURPOSE:An innovative chemical approach, named peptide welding technology (PWT), allows the synthesis of multibranched peptides with extraordinary high yield, purity and reproducibility. With this approach, three different tetrabranched derivatives of nociceptin/orphanin FQ (N/OFQ) have been synthesized ...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/bph.12799
更新日期：2014-09-01 00:00:00
abstract：:1 Contractions of the cat nictitating membrane were elicited on stimulation of the internal carotid nerve, and the effects were studied of desipramine and two inhibitors of catechol-O-methyltransferase, U-0521 and pyrogallol, on the subsequent relaxation of the muscle. 2 The relaxation of the nictitating membrane occu...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1978.tb07762.x
更新日期：1978-04-01 00:00:00
abstract：:1. The fall in arterial blood pressure with bradycardia that occurs on injection of clonidine into the cerebral ventricles and into the cisterna magna is attributed to an action on ;chemosensitive zones' situated at the ventral surface of the brain stem. This conclusion is based on the following results obtained in ca...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1973.tb08532.x
更新日期：1973-12-01 00:00:00
abstract：:1. This study describes the effects of hypoxia on relaxing responses and cAMP production induced by the known vasodilator peptides: alphaCGRP, amylin (AMY) and adrenomedullin (AM) on isolated pig coronary arteries in vitro. 2. Hypoxic incubation increased the vasorelaxant effect of alphaCGRP (four-fold; P<0.05), AMY (...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1038/sj.bjp.0706232
更新日期：2005-07-01 00:00:00
abstract：:Optimum assay conditions for the association of [3H]-para-tyramine [( 3H]-pTA) with rat brain membranes were characterized, and a saturable, reversible, drug-specific, and high affinity binding mechanism for this trace amine was revealed. The binding capacity (Bmax) for [3H]-pTA in the corpus striatum was approximatel...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1986.tb11116.x
更新日期：1986-09-01 00:00:00
abstract：:Relaxin is a small heterodimeric peptide hormone of the insulin/relaxin superfamily produced mainly in female and male reproductive organs. It has potent antifibrotic, vasodilatory and angiogenic effects and regulates the normal function of various physiological systems. Preclinical studies and recent clinical trials ...
journal_title：British journal of pharmacology
pub_type： 杂志文章,评审
doi：10.1111/bph.13656
更新日期：2017-05-01 00:00:00
abstract：:Some 865 genes in man encode G-protein-coupled receptors (GPCRs). The heterotrimeric guanine nucleotide-binding proteins (G-proteins) function to transduce signals from this vast panoply of receptors to effector systems including ion channels and enzymes that alter the rate of production, release or degradation of int...
journal_title：British journal of pharmacology
pub_type： 历史文章,杂志文章,评审
doi：10.1038/sj.bjp.0706405
更新日期：2006-01-01 00:00:00
abstract：:1. The effects of chronic oral administration of desmethylimipramine (DMI) or zimelidine (1.25 and 5 mg kg-1 twice daily for 21 days) were studied on rat whole cortical gamma-aminobutyric acidB (GABAB) binding sites. No changes in receptor affinity or number were found with either drug. 2. A subsequent study of GABAB ...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1988.tb11438.x
更新日期：1988-02-01 00:00:00
abstract：:Anthracyclines can cause cumulative dose-related cardiotoxicity characterized by changes in Ca(2+) metabolism, including dysfunction of the sacroplasmic reticulum (SR) and decreased expression of Ca(2+)-handling proteins, such as the ryanodine receptor (RyR2). In this study, we examined the effect of dexrazoxane (ICRF...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1038/sj.bjp.0703538
更新日期：2000-09-01 00:00:00
abstract：:We utilized a rat model of myocardial infarction to investigate whether manganese superoxide dismutase (Mn-SOD), an intrinsic radical scavenger, and tumour necrosis factor- alpha (TNF-alpha) and/or interleukin-1beta (IL-1beta) are involved in the late phase of ischaemic preconditioning (IP). IP was induced in anaesthe...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1038/sj.bjp.0703594
更新日期：2000-10-01 00:00:00
abstract：:1. Previous studies have shown that the histamine H(1) receptor activates p42/p44 mitogen-activated protein kinases (MAPK) in DDT(1)MF-2 smooth muscle cells via a phosphatidylinositol 3-kinase (PI-3K)-dependent pathway. In this study the effect of histamine H(1) receptor stimulation on protein kinase B (PKB) and p70 S...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1038/sj.bjp.0704664
更新日期：2002-04-01 00:00:00
abstract：:1. The present work describes the effects of inhibitors (amiloride and ethylisopropylamiloride) and activators (quinoxaline and phenylephrine) of the Na(+)-H+ exchanger on the outflow of dopamine in rat kidney slices loaded with L-dihydroxyphenylalanine (L-DOPA). 2. Incubation of kidney slices loaded with 50 microM L-...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1993.tb13608.x
更新日期：1993-06-01 00:00:00
abstract：:1. Chronic benzodiazepine administration has been associated with tolerance and with downregulation of gamma-aminobutyric acidA (GABAA)-receptor binding and function. However, effects of individual benzodiazepines on brain regions have varied. 2. To compare the effects of chronic lorazepam and alprazolam, we have admi...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1990.tb14167.x
更新日期：1990-12-01 00:00:00
abstract：:1. Hypercholesterolaemia often occurs in patients with type 2 diabetes, who therefore encounter administration of HMG-CoA reductase inhibitors. Alteration of pancreatic beta-cell function leading to an impaired insulin secretory response to glucose plays a crucial role in the pathogenesis of type 2 diabetes. Therefore...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1038/sj.bjp.0702397
更新日期：1999-03-01 00:00:00
abstract：:1. The effects of suramin on an adenosine 5'-triphosphate (ATP)-activated inward current were investigated in PC12 phaeochromocytoma cells with whole-cell voltage-clamp techniques. 2. Suramin (30 to 300 microM) inhibited the ATP-activated current in a dose-dependent manner. The inhibitory effects were reversible and c...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1990.tb12117.x
更新日期：1990-09-01 00:00:00
abstract：:1. The distribution of sympathetic adrenergic nerves on the rat middle cerebral artery and on the arterioles which originated from it was determined by use of gloxylic histochemistry. 2. Whereas the middle cerebral artery and proximal arterioles arising from this artery received a sympathetic innervation, the distal r...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1989.tb11884.x
更新日期：1989-04-01 00:00:00
abstract：:1. We have compared the effects of ouabain on the maintenance of gap junctional communication in rat aortic A7r5 smooth muscle cells, monkey COS-1 fibroblasts and human HeLa epithelial cells. 2. Ouabain (1 mM) interrupted dye coupling between confluent A7r5 cells within approximately 1 h, and high concentrations of ou...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1038/sj.bjp.0705556
更新日期：2003-12-01 00:00:00
abstract：BACKGROUND AND PURPOSE:Although botulinum toxin type A (BoNT/A) is approved for chronic migraine treatment, its mechanism of action is still unknown. Dural neurogenic inflammation (DNI) commonly used to investigate migraine pathophysiology can be evoked by trigeminal pain. Here, we investigated the reactivity of crania...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/bph.13366
更新日期：2016-01-01 00:00:00
abstract：:The concentrations of catecholamines and the activities of dopamine-beta-hydroxylase were measured in blood obtained from decapitated diabetic and aged-matched control rats. The activity of dopamine-beta-hydroxylase in blood from diabetic rats was much greater (5 fold) than that seen for control rats. For both diabeti...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1978.tb08632.x
更新日期：1978-09-01 00:00:00
abstract：:1. The intravenous infusion of I.C.I. 50172 in doses up to 20 mg reduced, although not significantly, the increase in heart rate produced by the infusion of isoprenaline in healthy volunteers; the response to adrenaline was significantly reduced. The infusion of 1 mg propranolol abolished these responses2. After the p...
journal_title：British journal of pharmacology
pub_type： 临床试验,杂志文章
doi：10.1111/j.1476-5381.1968.tb07956.x
更新日期：1968-09-01 00:00:00
abstract：:Histamine-induced contractions of small airways from human lung were substantially augmented by the cyclo-oxygenase inhibitor, indomethacin, whereas the contraction of larger airways was not. Mixed cyclo-oxygenase/lipoxygenase inhibitors of arachidonic acid metabolism did not modify histamine-induced contractions of s...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1982.tb09333.x
更新日期：1982-12-01 00:00:00
abstract：:1. Piperazinylindoles (DPI 201-106, BDF 8784), drugs known to act on voltage-dependent Na(+)-channels, bind with very high affinity to a Ca2(+)-channel-associated phenylalkylamine receptor in Drosophila melanogaster head membranes. These compounds and (+)-tetrandrine, a naturally occurring Ca2(+)-antagonist, were the ...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1991.tb12193.x
更新日期：1991-02-01 00:00:00
abstract：:1. Immunohistochemical and functional studies have been performed to localize and determine the effects of neuropeptide Y (NPY) in the rat seminal vesicle. 2. An abundant presence of NPY-immunoreactive nerves, mainly concentrated in the smooth muscle layer of the seminal vesicle was found. Chronic 6-hydroxydopamine tr...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1994.tb17074.x
更新日期：1994-11-01 00:00:00
abstract：:1. Contractile responses to short trains of nerve stimulation have been characterized in small, medium and large arteries from the rat mesenteric circulation (5th - 6th, 2nd - 3rd and 1st order, respectively). In addition, sources of calcium for smooth muscle contraction have been investigated. 2. Nerve stimulation (1...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1038/sj.bjp.0703925
更新日期：2001-03-01 00:00:00
abstract：:The binding of DL-[3,4-3H] 2-amino-4-phosphonobutyric acid DL[3H]-APB to rat whole brain synaptic membranes was investigated. Binding was linear with membrane protein concentration, and optimal at physiological pH and temperature. The association rate was rapid, achieving equilibrium within 10 min. Prolonged incubatio...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1983.tb10041.x
更新日期：1983-10-01 00:00:00
abstract：:The effect of leukaemia inhibitory factor (LIF) in modulating cholinergic and sensory nerve function was examined using guinea-pig tracheal explants. Specific LIF receptors (LIFR) were immunolocalized to both cholinergic and sensory nerves. Release of SP in culture was not influenced by LIF. Similarly, maximum contrac...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1038/sj.bjp.0703415
更新日期：2000-07-01 00:00:00
abstract：BACKGROUND AND PURPOSE:Sublesional osteoporosis predisposes individuals with spinal cord injury (SCI) to an increased risk of low-trauma fracture. The aim of the present work was to investigate the effect of treatment with resveratrol (RES) on sublesional bone loss in spinal cord-injured rats. EXPERIMENTAL APPROACH:Co...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/bph.12301
更新日期：2013-10-01 00:00:00
abstract：:The sensitivity of the uterus to the inhibition of contractions by salbutamol, diltiazem or nifedipine was assessed in the ovariectomized, post-partum rat by dose-response curves following bolus intravenous (i.v.) administration. These tests were performed before (day 1), immediately after a 20 h i.v. infusion of salb...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1986.tb10238.x
更新日期：1986-07-01 00:00:00
abstract：:1. Adenosine A(1), A(2A), and A(3) receptors (ARs) and extracellular signal-regulated kinase 1/2 (ERK1/2) play a major role in myocardium protection from ischaemic injury. In this study, we have characterized the adenosine receptor subtypes involved in ERK1/2 activation in newborn rat cardiomyocytes. 2. Adenosine (non...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1038/sj.bjp.0705614
更新日期：2004-01-01 00:00:00
abstract：:The effects of the opioid receptor agonist RX783006 and of the opioid receptor partial agonist (+)-meptazinol have been examined on electrically induced twitch responses of the guinea-pig isolated ileum and of the mouse isolated vas deferens. Log10 concentration-tissue state curves were determined for (+)-meptazinol a...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1986.tb10246.x
更新日期：1986-07-01 00:00:00
