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Acetylcholine Signaling System in Progression of Lung Cancers

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Acetylcholine Signaling System in Progression of Lung Cancers Pharmacology & Therapeutics 194 (2019) 222–254 Contents lists available at ScienceDirect Pharmacology & Therapeutics journal homepage: www.elsevier.com/locate/pharmthera Acetylcholine signaling system in progression of lung cancers Jamie R. Friedman a,1, Stephen D. Richbart a,1,JustinC.Merritta,KathleenC.Browna, Nicholas A. Nolan a, Austin T. Akers a, Jamie K. Lau b, Zachary R. Robateau a, Sarah L. Miles a,PiyaliDasguptaa,⁎ a Department of Biomedical Sciences, Joan C. Edwards School of Medicine, 1700 Third Avenue, Huntington, WV 25755 b Biology Department, Center for the Sciences, Box 6931, Radford University, Radford, Virginia 24142 article info abstract Available online 3 October 2018 The neurotransmitter acetylcholine (ACh) acts as an autocrine growth factor for human lung cancer. Several lines of evidence show that lung cancer cells express all of the proteins required for the uptake of choline (choline Keywords: transporter 1, choline transporter-like proteins) synthesis of ACh (choline acetyltransferase, carnitine acetyl- Lung cancer transferase), transport of ACh (vesicular acetylcholine transport, OCTs, OCTNs) and degradation of ACh (acetyl- Acetylcholine cholinesterase, butyrylcholinesterase). The released ACh binds back to nicotinic (nAChRs) and muscarinic Cholinergic receptors on lung cancer cells to accelerate their proliferation, migration and invasion. Out of all components Proliferation of the cholinergic pathway, the nAChR-signaling has been studied the most intensely. The reason for this trend Invasion Anti-cancer drugs is due to genome-wide data studies showing that nicotinic receptor subtypes are involved in lung cancer risk, the relationship between cigarette smoke and lung cancer risk as well as the rising popularity of electronic ciga- rettes considered by many as a “safe” alternative to smoking. There are a small number of articles which review the contribution of the other cholinergic proteins in the pathophysiology of lung cancer. The primary objective of this review article is to discuss the function of the acetylcholine-signaling proteins in the progression of lung can- cer. The investigation of the role of cholinergic network in lung cancer will pave the way to novel molecular tar- gets and drugs in this lethal malignancy. © 2018 Elsevier Inc. All rights reserved. Contents Listofabbreviationsused3ormoretimes................................... 223 1. Introduction..............................................223 2. Acetylcholine(ACh)..........................................225 3. CholineTransporters(ChTs).......................................229 227 4. MuscarinicReceptors..........................................232 229 5. NicotinicReceptors(nAChRs)......................................235 229 6. Lymphocyte Antigen 6 (Ly-6) Proteins as allosteric modulators of Nicotinic Acetylcholine Receptor (nAChR): Lynx and Se- cretedly6/urokinase-typeplasminogenactivatorreceptorrelatedpeptide(SLURP)..............240 230 7. Cholinesterases(ChEs).........................................242 232 8. Conclusionsandfuturedirections....................................245 235 Acknowledgements.............................................247 240 References.................................................247 242 ⁎ Corresponding author at: Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, 1700 3rd Avenue, Huntington, WV 25755 E-mail address: [email protected] (P. Dasgupta). 1 These authors contributed equally to the work presented here and should therefore be regarded as equivalent authors. https://doi.org/10.1016/j.pharmthera.2018.10.002 0163-7258/© 2018 Elsevier Inc. All rights reserved. J.R. Friedman et al. / Pharmacology & Therapeutics 194 (2019) 222–254 223 List of abbreviations used 3 or more times α-NETA 2-(alpha-naphthoyl)ethyltrimethylammonium ACh Acetylcholine AChE Acetylcholinesterase or acetylcholineacetylhydrolase AFDX-116 {11-[[2-[(Diethylamino)methyl]-1-piperidinyl] acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4] benzodiazepin-6-one} BAC Bronchioalveolar carcinoma BChE Butyrylcholinesterase or acylcholine acylhydrolase BCX β-Cryptoxanthin BECs Bronchial epithelial cells BrdU Bromodeoxyuridine CarAT Carnitine acetyltransferase ChAT Choline acetyltransferase ChE Cholinesterase ChT Choline transporter ChT1/SLC5A7 High affinity choline transporter 1 COPD Chronic obstructive pulmonary disease CTL1-5 Choline transporter-like proteins 1-5 EGF Epidermal growth factor EGFR Epidermal growth factor receptor EMT Epithelial-to-mesenchymal transition ERK Extracellular related kinase H69 NCI-H69 H82 NCI-H82 HC-3 Hemicholinium-3 HMEC-L Human microvascular endothelial cells of the lung hsa-miR-132 microRNA-132 HUVECs Human umbilical cord microvascular endothelial cells Fig. 1. The spectrum of malignancies which comprise lung cancers. Small cell lung cancer IGF-2 Insulin growth factor-2 (SCLC; also called oat cell carcinoma) comprises of morphologically tiny cells. All other lung LAC Lung adenocarcinoma malignancies are put into a heterogenous group termed non-small cell lung cancer LCC Large cell carcinoma (NSCLC). Out of NSCLCs lung adenocarcinoma (LAC) accounts for majority of cases Ly-6 Lymphocyte antigen 6 followed by squamous cell carcinoma of the lung (SCC-L). Large cell carcinoma (LCC) and M1R to M5R Muscarinic Receptor 1-5 neuroendocrine carcinoid tumors of the lung are relatively less common than LAC and SCC-Ls. MAPK Mitogen activated protein kinase MMP Matrix metalloproteinases MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) carcinoma (BAC). According to the new WHO classification, BAC is now nAChR Nicotinic acetylcholine receptors included in the category of LAC. SCC-Ls usually develop in the tissues com- NEP Norepinephrine prising the air passages of the lung. Due to cigarette smoking, SCC-L is NHBE Normal bronchial epithelial cells NNK Nicotine-derived nitrosamine ketone, often preceded by a columnar-to-squamous metaplasia, which lasts for 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone years before developing into an in situ carcinoma (Soldera & Leighl, NSCLC Non-small cell lung cancer 2017). Traditionally SCC-L has also been called as epidermoid carcinoma, OAT Organic anion transporter arising in central large bronchi which join the trachea to the lung. OCT Organic cation transporter Epidemiological data indicates that cigarette smoking bears a strong OCT1-3/SLC22A1-2 Polyspecific organic transporters OCTN1 and OCTN2 Carnitine/cation transporters etiological association with the development of all histological types of PI-3 kinase Phosphoinositol-3 kinase lung cancer (Furrukh, 2013). The association between smoking and poly-APS 3-alkyl pyridium polymers lung cancer is stronger with SCLC and SCC-L than with other forms of SAEC Primary small airway epithelial cells lung cancer (Khuder, 2001; Khuder & Mutgi, 2001). Nicotine is the ad- SCC-L Squamous cell carcinoma of the lung SCLC Small cell lung cancer dictive component of cigarette smoke. Several lines of evidence show shRNA Short-hairpin RNA that nicotine accelerates the growth, angiogenesis and metastasis of siRNA Small interfering RNA lung cancers (Dasgupta & Chellappan, 2006; Dasgupta et al., 2011; SLURP Secreted ly6/urokinase-type plasminogen activator receptor Dasgupta et al., 2009; Davis et al., 2009; C Heeschen et al., 2001; C. related peptide Heeschen, Weis, Aicher, Dimmler, & Cooke, 2002; Singh, Pillai, & SNPs Single nucleotide polymorphisms STAT3 Signal transducer and activator of transcription 3 Chellappan, 2011; Spindel, 2016; Zoli, Pucci, Vilella, & Gotti, 2018). Fur- TGF-β1 Transforming growth factor β1 thermore, nicotine protects lung cancers from cell death induced by VAChT Vesicular acetylcholine transporter chemotherapeutic drugs, oxidative stress and ionizing radiation VEGF Vascular endothelial growth factor (Dasgupta, Kinkade, et al., 2006; Egleton, Brown, & Dasgupta, 2008; Jin, Gao, Flagg, & Deng, 2004; Mai, May, Gao, Jin, & Deng, 2003; 1. Introduction Maneckjee & Minna, 1994; West, Linnoila, Belinsky, Harris, & Dennis, 2004; Zeidler, Albermann, & Lang, 2007). The growth-stimulatory ef- Lung cancer is comprised of a spectrum of malignancies. Small cell fects of nicotine are mediated via nicotinic acetylcholine receptors lung cancer (SCLC; formerly known as oat cell carcinoma) is a neuroendo- (nAChRs) on lung tumors and the surrounding stroma (S. Wang & Hu, crine carcinoma and accounts for about 15-20% of all lung cancer cases 2018; Zhao, 2016; Zoli et al., 2018). The endogenous ligand for nAChRs (Gazdar, Bunn, & Minna, 2017). All other forms of lung cancers are in- is the neurotransmitter acetylcholine (ACh; Kirkpatrick et al., 2001; cluded in a heterogeneous group called non-small cell lung cancer Kummer & Krasteva-Christ, 2014; Mucchietto, Crespi, Fasoli, Clementi, (NSCLC). NSCLC includes lung adenocarcinoma (LAC), squamous cell car- & Gotti, 2016; Niu & Lu, 2014; Saracino, Zorzetto, Inghilleri, Pozzi, & cinoma (SCC-L), large cell carcinoma (LCC) and neuroendocrine lung car- Stella, 2013). Genome-wide association studies (GWAS) identified a ge- cinoid tumors (Fig. 1; Doroshow & Herbst, 2018; Herbst, Morgensztern, & netic component of the association between tobacco components and Boshoff, 2018). LAC originates from the mucus secreting glands in the the development of lung cancer. Data collected from European popula- lungs (Meza, Meernik, Jeon, & Cote, 2015). A substantial number of early tions have discovered a locus in the long arm of chromosome 15 published reports involved
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