BCH, an Inhibitor of System L Amino Acid Transporters, Induces Apoptosis in Cancer Cells

• Published in: Biological & Pharmaceutical Bulletin Vol. 31; no. 6; pp. 1096 - 1100
• Main Authors: Kim, Chun Sung, Cho, Seon-Ho, Chun, Hong Sung, Lee, Sook-Young, Endou, Hitoshi, Kanai, Yoshikatsu, Kim, Do Kyung
• Format: Journal Article
• Language: English
• Published: Japan The Pharmaceutical Society of Japan 01.06.2008; Pharmaceutical Society of Japan; Japan Science and Technology Agency
• Subjects: 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid; Actins - biosynthesis; Actins - genetics; Amino Acid Transport Systems - antagonists & inhibitors; Amino Acids, Cyclic - pharmacology; anti-cancer therapy; Antineoplastic Agents; apoptosis; Apoptosis - drug effects; Blotting, Western; cancer cell; Caspases - metabolism; Cell Division - drug effects; Cell Line, Tumor; DNA Fragmentation; Enzyme Activation - drug effects; Humans; In Situ Nick-End Labeling; KB Cells; L-type amino acid transporter; Large Neutral Amino Acid-Transporter 1 - genetics; Large Neutral Amino Acid-Transporter 1 - metabolism; Leucine - metabolism; Tetrazolium Salts; Thiazoles
• ISSN: 0918-6158; 1347-5215
• DOI: 10.1248/bpb.31.1096

Purpose: L-Type amino acid transporter 1 (LAT1) is highly expressed in cancer cells to support their continuous growth and proliferation. We have examined the effect of 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH), an inhibitor of system L amino acid transporters, and the mechanism by which BCH suppresses cell growth in cancer cells. Methods: The effect of BCH and the mechanism of BCH on cell growth suppression in cancer cells were examined using amino acid transport measurement, MTT assay, DNA fragmentation analysis, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay and immunoblotting. Results: BCH inhibited L-leucine transport in a concentration-dependent manner, and it inhibited cell growth in a time-dependent manner in KB human oral epidermoid carcinoma cells, Saos2 human osteogenic sarcoma cells and C6 rat glioma cells. The formation of a DNA ladder was observed, and the number of TUNEL-positive cells was increased with BCH treatment. Furthermore, the proteolytic processing of caspase-3 in KB and C6 cells and of caspase-7 in KB, Saos2 and C6 cells was increased by BCH treatment. Conclusion: These results suggest that the inhibition of LAT1 activity by BCH leads to apoptotic cancer cell death by inducing intracellular depletion of neutral amino acids necessary for cancer cell growth.