1. Efficacy of system <scp>l</scp> amino acid transporter 1 inhibition as a therapeutic target in esophageal squamous cell carcinoma
- Author
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Tatsuya Miyazaki, Noriko S. Ishioka, Hideyuki Tominaga, Yoshikatsu Kanai, Noboru Oriuchi, Shushi Nagamori, Aiko Yamaguchi, Kyoichi Kaira, Yoshito Tsushima, Takehiko Yokobori, Hiroyuki Kuwano, Takayuki Asao, and Yasuhiro Ohshima
- Subjects
Male ,0301 basic medicine ,Cancer Research ,Cell cycle checkpoint ,Esophageal Neoplasms ,Fusion Regulatory Protein-1 ,molecular target ,Mice ,chemistry.chemical_compound ,0302 clinical medicine ,Molecular Targeted Therapy ,esophageal cancer ,Amino Acids ,biology ,TOR Serine-Threonine Kinases ,General Medicine ,Esophageal cancer ,system l amino acid transporter 1 ,Oncology ,Biochemistry ,030220 oncology & carcinogenesis ,Carcinoma, Squamous Cell ,Original Article ,Esophageal Squamous Cell Carcinoma ,Signal transduction ,Growth inhibition ,Signal Transduction ,CD98 ,Antineoplastic Agents ,03 medical and health sciences ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Lactate Dehydrogenases ,Cell Proliferation ,mammalian target of rapamycin ,2‐Aminobicyclo‐(2,2,1)‐heptane‐2‐carboxylic acid ,Cell growth ,Gene Expression Profiling ,Cancer ,Biological Transport ,Cell Cycle Checkpoints ,Original Articles ,medicine.disease ,Xenograft Model Antitumor Assays ,Disease Models, Animal ,Drug Discovery and Delivery ,030104 developmental biology ,chemistry ,Cell culture ,Amino Acid Transport System L ,biology.protein ,Cancer research ,Transcriptome - 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-14 C-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 G1 phase. 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.
- Published
- 2016