title: Efficacy of system l amino acid transporter 1 inhibition as a therapeutic target in esophageal squamous cell carcinoma.
abstract: System l amino acid transporter 1 (LAT1) is highly expressed in various types of human cancer, and contributes to cancer growth and survival. Recently, we have shown that LAT1 expression is closely related to the growth and aggressiveness of esophageal cancer, and is an independent marker of poor prognosis. However, it remains unclear whether LAT1 inhibition could suppress esophageal cancer growth. In this study, we investigated the tumor-suppressive effects of the inhibition of LAT1. Both LAT1 and CD98, which covalently associates to LAT1 on the membrane, were expressed in human esophageal cancer cell lines KYSE30 and KYSE150. Quantitative PCR analysis showed that the expression of LAT1 was much higher than other subtypes of LAT. A selective inhibitor of LAT, 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH), suppressed cellular uptake of l-14C-leucine and cell proliferation in a dose-dependent manner. It also suppressed phosphorylation of mammalian target of rapamycin, 4E-BP1, and p70S6K protein, and induced cell cycle arrest at G1phase. These results suggest that suppression of both mammalian target of rapamycin signaling and cell cycle progression is involved in BCH-induced growth inhibition. In tumor-bearing mice, daily treatment with BCH significantly delayed tumor growth and decreased glucose metabolism, indicating that LAT1 inhibition potentially suppresses esophageal cancer growth in vivo. Thus, our results suggest that LAT1 inhibition could be a promising molecular target for the esophageal cancer therapy.
authors.affiliation: Department of Radiation-Applied Biology Research, Quantum Beam Science Research Directorate, National Institutes for Quantum and Radiological Science and Technology, Takasaki, Japan. b16gradmmptimp@yahoo.co.jp.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Ohshima
authors.affiliation: Department of Oncology Clinical Development, Gunma University Graduate School of Medicine, Maebashi, Japan.
authors.forename: Kyoichi
authors.initials: K
authors.lastname: Kaira
authors.affiliation: Department of Bioimaging Information Analysis, Gunma University Graduate School of Medicine, Maebashi, Japan.
authors.forename: Aiko
authors.initials: A
authors.lastname: Yamaguchi
authors.affiliation: Advanced Clinical Research Center, Fukushima Medical University, Fukushima, Japan.
authors.forename: Noboru
authors.initials: N
authors.lastname: Oriuchi
authors.affiliation: Advanced Clinical Research Center, Fukushima Medical University, Fukushima, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Tominaga
authors.affiliation: Division of Bio-system Pharmacology, Graduate School of Medicine, Osaka University, Suita, Japan.
authors.forename: Shushi
authors.initials: S
authors.lastname: Nagamori
authors.affiliation: Division of Bio-system Pharmacology, Graduate School of Medicine, Osaka University, Suita, Japan.
authors.forename: Yoshikatsu
authors.initials: Y
authors.lastname: Kanai
authors.affiliation: Department of Molecular Pharmacology and Oncology, Gunma University Graduate School of Medicine, Maebashi, Japan.
authors.forename: Takehiko
authors.initials: T
authors.lastname: Yokobori
authors.affiliation: Department of General Surgical Science, Gunma University Graduate School of Medicine, Maebashi, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Miyazaki
authors.affiliation: Department of Oncology Clinical Development, Gunma University Graduate School of Medicine, Maebashi, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Asao
authors.affiliation: Department of Diagnostic Radiology and Nuclear Medicine, Gunma University Graduate School of Medicine, Maebashi, Japan.
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Tsushima
authors.affiliation: Department of General Surgical Science, Gunma University Graduate School of Medicine, Maebashi, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kuwano
authors.affiliation: Department of Radiation-Applied Biology Research, Quantum Beam Science Research Directorate, National Institutes for Quantum and Radiological Science and Technology, Takasaki, Japan.
authors.forename: Noriko S
authors.initials: NS
authors.lastname: Ishioka
mesh_terms: D027062:Amino Acid Transport System L / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004938:Esophageal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000077277:Esophageal Squamous Cell Carcinoma; D027261:Fusion Regulatory Protein-1 / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D045022:Lactate Dehydrogenases / Q000378:metabolism; D008297:Male; D051379:Mice; D058990:Molecular Targeted Therapy; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D059467:Transcriptome; D023041:Xenograft Model Antitumor Assays
chemical_list: D027062:Amino Acid Transport System L; D000596:Amino Acids; D000970:Antineoplastic Agents; D027261:Fusion Regulatory Protein-1; D045022:Lactate Dehydrogenases; D058570:TOR Serine-Threonine Kinases
keywords: 2-Aminobicyclo-(2,2,1)-heptane-2-carboxylic acid; esophageal cancer; mammalian target of rapamycin; molecular target; system l amino acid transporter 1