title: Targeting SLC1a5-mediated glutamine dependence in non-small cell lung cancer.
abstract: We previously elucidated the pleotropic role of solute carrier family A1 member 5 (SLC1A5) as the primary transporter of glutamine (Gln), a modulator of cell growth and oxidative stress in non-small cell lung cancer (NSCLC). The aim of our study was to evaluate SLC1A5 as a potential new therapeutic target and candidate biomarker predictive of survival and response to therapy. SLC1A5 targeting was examined in a panel of NSCLC and human bronchial cell lines by RNA interference and by a small molecular inhibitor, gamma-l-glutamyl-p-nitroanilide (GPNA). The effects of targeting SLC1A5 on cell growth, Gln uptake, ATP level, autophagy and cell death were examined. Inactivation of SLC1A5 genetically or pharmacologically decreased Gln consumption, inhibited cell growth, induced autophagy and apoptosis in a subgroup of NSCLC cell lines that overexpress SLC1A5. Targeting SLC1A5 function decreased tumor growth in NSCLC xenografts. A multivariate Cox proportional hazards analysis indicates that patients with increased SLC1A5 mRNA expression have significantly shorter overall survival (p = 0.01, HR = 1.24, 95% CI: 1.05-1.46), adjusted for age, gender, smoking history and disease stage. In an immunohistochemistry study on 207 NSCLC patients, SLC1A5 protein expression remained highly significant prognostic value in both univariate (p < 0.0001, HR = 1.45, 95% CI: 1.15-1.50) and multivariate analyses (p = 0.04, HR = 1.22, 95% CI: 1.01-1.31). These results position SLC1A5 as a new candidate prognostic biomarker for selective targeting of Gln-dependent NSCLC.
authors.affiliation: Thoracic Program, Vanderbilt-Ingram Comprehensive Cancer Center and Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University, Nashville, TN.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Hassanein
authors.affiliation: Thoracic Program, Vanderbilt-Ingram Comprehensive Cancer Center and Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University, Nashville, TN.
authors.forename: Jun
authors.initials: J
authors.lastname: Qian
authors.affiliation: Thoracic Program, Vanderbilt-Ingram Comprehensive Cancer Center and Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University, Nashville, TN.
authors.forename: Megan D
authors.initials: MD
authors.lastname: Hoeksema
authors.affiliation: Department of Biomedical Informatics, Vanderbilt University, Nashville, TN.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Thoracic Program, Vanderbilt-Ingram Comprehensive Cancer Center and Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University, Nashville, TN.
authors.forename: Marie
authors.initials: M
authors.lastname: Jacobovitz
authors.affiliation: Thoracic Program, Vanderbilt-Ingram Comprehensive Cancer Center and Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University, Nashville, TN.
authors.forename: Xiangming
authors.initials: X
authors.lastname: Ji
authors.affiliation: Thoracic Program, Vanderbilt-Ingram Comprehensive Cancer Center and Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University, Nashville, TN.|Department of Biochemistry and Cancer Biology, Meharry Medical College, Nashville, TN.
authors.forename: Fredrick T
authors.initials: FT
authors.lastname: Harris
authors.affiliation: Thoracic Program, Vanderbilt-Ingram Comprehensive Cancer Center and Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University, Nashville, TN.
authors.forename: Bradford K
authors.initials: BK
authors.lastname: Harris
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, TN.
authors.forename: Kelli L
authors.initials: KL
authors.lastname: Boyd
authors.affiliation: Department of Biostatistics, Vanderbilt University, Nashville, TN.
authors.forename: Heidi
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, TN.
authors.forename: Rosana
authors.initials: R
authors.lastname: Eisenberg
authors.affiliation: Thoracic Program, Vanderbilt-Ingram Comprehensive Cancer Center and Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University, Nashville, TN.|Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN.
authors.forename: Pierre P
authors.initials: PP
authors.lastname: Massion
mesh_terms: D026962:Amino Acid Transport System ASC / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism* / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D055785:Gene Knockdown Techniques; D005973:Glutamine / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000628:therapy*; D051379:Mice; D015778:Minor Histocompatibility Antigens; D058990:Molecular Targeted Therapy; D011379:Prognosis; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D026962:Amino Acid Transport System ASC; D015778:Minor Histocompatibility Antigens; D034741:RNA, Small Interfering; C420506:SLC1A5 protein, human; D005973:Glutamine
keywords: biomarker; glutamine transporters; lung cancer
references.citation: J Biol Chem. 2001 Jan 26;276(4):2780-5
references.pmid: 11054413
references.citation: Cancer Res. 2002 Jul 1;62(13):3636-40
references.pmid: 12097266
references.citation: Am J Physiol Gastrointest Liver Physiol. 2004 Mar;286(3):G467-78
references.pmid: 14563674
references.citation: Cancer Res. 1979 Aug;39(8):3220-4
references.pmid: 572261
references.citation: Cancer Res. 1986 Feb;46(2):798-806
references.pmid: 3940644
references.citation: Br J Cancer. 1987 Jun;55(6):653-6
references.pmid: 3620309
references.citation: Biochem J. 1988 Jan 15;249(2):443-9
references.pmid: 3342022
references.citation: Pharmacol Ther. 1990;46(2):243-71
references.pmid: 2108451
references.citation: Br J Cancer. 1996 May;73(10):1193-200
references.pmid: 8630278
references.citation: Yeast. 2005 Jun;22(8):641-52
references.pmid: 16034825
references.citation: Drug Resist Updat. 2005 Jun;8(3):163-70
references.pmid: 15946892
references.citation: Drug Resist Updat. 2007 Dec;10(6):235-55
references.pmid: 18180198
references.citation: Biol Pharm Bull. 2008 Jun;31(6):1096-100
references.pmid: 18520037
references.citation: Mol Cancer Ther. 2009 Jan;8(1):101-9
references.pmid: 19139118
references.citation: Cell. 2009 Feb 6;136(3):521-34
references.pmid: 19203585
references.citation: Mol Syst Biol. 2011;7:523
references.pmid: 21847114
references.citation: J Med Chem. 2011 Jan 13;54(1):406-10
references.pmid: 21128591
references.citation: J Nucl Med. 2011 Dec;52(12):1947-55
references.pmid: 22095958
references.citation: Nature. 2012 Jan 19;481(7381):380-4
references.pmid: 22101433
references.citation: CA Cancer J Clin. 2012 Jul-Aug;62(4):220-41
references.pmid: 22700443
references.citation: Cancer Res. 2012 Sep 1;72(17):4526-36
references.pmid: 22773663
references.citation: Mol Cell Proteomics. 2012 Oct;11(10):916-32
references.pmid: 22761400
references.citation: J Nucl Med. 2012 Oct;53(10):1616-24
references.pmid: 22935578
references.citation: Clin Cancer Res. 2013 Feb 1;19(3):560-70
references.pmid: 23213057
references.citation: Nature. 2013 Apr 4;496(7443):101-5
references.pmid: 23535601
references.citation: Genes Dev. 2013 Jul 1;27(13):1447-61
references.pmid: 23824538
references.citation: J Clin Invest. 2013 Sep;123(9):3678-84
references.pmid: 23999442
references.citation: Cancer Cell. 2013 Oct 14;24(4):450-65
references.pmid: 24094812
references.citation: Cancer Discov. 2013 Nov;3(11):1272-85
references.pmid: 23965987
references.citation: PLoS One. 2013;8(12):e82241
references.pmid: 24367507
references.citation: Sci Transl Med. 2014 Jan 29;6(221):221ra15
references.pmid: 24477002