BCH, an inhibitor of system L amino acid transporters, induces apoptosis in cancer cells
BCH, an inhibitor of system L amino acid transporters, induces apoptosis in cancer cells
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DOI：
10.1248/bpb.31.1096
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发表时间：
2008-06-01
影响因子：
2
通讯作者：
Kim, Do Kyung
中科院分区：
文献类型：
--
作者：
Kim, Chun Sung;Cho, Seon-Ho;Kim, Do Kyung
目的：L氨基酸转运蛋白1(LAT1)在肿瘤细胞中高表达，支持肿瘤细胞的持续生长和增殖。我们研究了L氨基酸转运蛋白系统的抑制剂2-氨基双环-(2，2，1)-庚烷-2-羧酸的作用及其抑制癌细胞生长的机制。方法：采用氨基酸转运测定、四甲基偶氮唑盐比色法、DNA片段化分析、末端脱氧核苷酸转移酶介导的dUTP缺口末端标记法和免疫印迹法检测BCH对癌细胞生长的抑制作用及其机制。结果：BCH以浓度依赖方式抑制L亮氨酸转运，以时间依赖方式抑制KB人口腔上皮样癌细胞、Saos2人骨肉瘤细胞和C6大鼠神经胶质瘤细胞的生长。BCH处理后可见DNA梯状条带形成，TUNEL阳性细胞数增加。此外，BCH还促进了Kb和C6细胞中caspase-3的蛋白降解过程以及Kb、Saos2和C6细胞中caspase-7的蛋白降解过程。结论：BCH对LAT1活性的抑制可能通过诱导癌细胞生长所必需的中性氨基酸的胞内表达而导致癌细胞死亡。
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 depiction of neutral amino acids necessary for cancer cell growth.