title: Amino acid transporter SLC6A14 is a novel and effective drug target for pancreatic cancer.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Augusta University, Augusta, GA, 30912, USA.
authors.forename: V
authors.initials: V
authors.lastname: Coothankandaswamy
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Cao
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Biochemistry and Molecular Biology, Augusta University, Augusta, GA, 30912, USA.
authors.forename: P D
authors.initials: PD
authors.lastname: Prasad
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: P K
authors.initials: PK
authors.lastname: Singh
authors.affiliation: Department of Cell Biology and Biochemistry and Cancer Center, Texas Tech University Health Sciences Center, Lubbock, TX, 30912, USA.
authors.forename: C P
authors.initials: CP
authors.lastname: Reynolds
authors.affiliation: Department of Cell Biology and Biochemistry and Cancer Center, Texas Tech University Health Sciences Center, Lubbock, TX, 30912, USA.
authors.forename: S
authors.initials: S
authors.lastname: Yang
authors.affiliation: Department of Cell Biology and Biochemistry and Cancer Center, Texas Tech University Health Sciences Center, Lubbock, TX, 30912, USA.
authors.forename: J
authors.initials: J
authors.lastname: Ogura
authors.affiliation: Department of Cell Biology and Biochemistry and Cancer Center, Texas Tech University Health Sciences Center, Lubbock, TX, 30912, USA.
authors.forename: V
authors.initials: V
authors.lastname: Ganapathy
authors.affiliation: Department of Cell Biology and Biochemistry and Cancer Center, Texas Tech University Health Sciences Center, Lubbock, TX, 30912, USA.
authors.forename: Y D
authors.initials: YD
authors.lastname: Bhutia
mesh_terms: D026905:Amino Acid Transport Systems; D026921:Amino Acid Transport Systems, Neutral / Q000037:antagonists & inhibitors / Q000235:genetics*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D014364:Tryptophan / Q000031:analogs & derivatives* / Q000494:pharmacology; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
chemical_list: D026905:Amino Acid Transport Systems; D026921:Amino Acid Transport Systems, Neutral; D000970:Antineoplastic Agents; D012333:RNA, Messenger; C503995:SLC6A14 protein, human; C020774:alpha-methyltryptophan; D014364:Tryptophan