BCH, an inhibitor of system L amino acid transporters, induces apoptosis in cancer cells.
OBJECTIVE
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.


CONCLUSIONS
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.
Department of Oral Physiology and The Second Stage of BK21, Chosun University College of Dentistry, Seosuk-dong, Gwangju, Korea.
Chun Sung
CS
Kim
Seon-Ho
SH
Cho
Hong Sung
HS
Chun
Sook-Young
SY
Lee
Hitoshi
H
Endou
Yoshikatsu
Y
Kanai
Do Kyung
DK
Kim
D000199:Actins / Q000096:biosynthesis / Q000235:genetics; D026905:Amino Acid Transport Systems / Q000037:antagonists & inhibitors*; D000598:Amino Acids, Cyclic / Q000494:pharmacology*; D000970:Antineoplastic Agents; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D053938:DNA Fragmentation; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D020287:In Situ Nick-End Labeling; D007624:KB Cells; D027283:Large Neutral Amino Acid-Transporter 1 / Q000235:genetics / Q000378:metabolism; D007930:Leucine / Q000378:metabolism; D013778:Tetrazolium Salts; D013844:Thiazoles
D000199:Actins; D026905:Amino Acid Transport Systems; D000598:Amino Acids, Cyclic; D000970:Antineoplastic Agents; D027283:Large Neutral Amino Acid-Transporter 1; D013778:Tetrazolium Salts; D013844:Thiazoles; C006504:2-aminobicyclo(2,2,1)heptane-2-carboxylic acid; D020169:Caspases; C022616:thiazolyl blue; D007930:Leucine