Targeting Amino Acid Transport in Metastatic Castration-Resistant Prostate Cancer: Effects on Cell Cycle, Cell Growth, and Tumor Development
Targeting Amino Acid Transport in Metastatic Castration-Resistant Prostate Cancer: Effects on Cell Cycle, Cell Growth, and Tumor Development
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DOI：
10.1093/jnci/djt241
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发表时间：
2013-10-01
影响因子：
10.3
通讯作者：
Holst, Jeff
中科院分区：
文献类型：
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作者：
Wang, Qian;Tiffen, Jessamy;Holst, Jeff
背景L型氨基酸转运蛋白（LATs）可将L-亮氨酸等中性氨基酸摄取到细胞内，刺激哺乳动物雷帕霉素复合物1靶蛋白的信号传导和蛋白质合成。LAT 1和LAT 3在前列腺癌的不同阶段过表达，它们负责增加营养和刺激细胞growth.Methods我们研究了LAT 3蛋白在人前列腺癌组织微阵列中的表达。LAT功能抑制使用亮氨酸类似物（BCH）在雄激素依赖性和非依赖性的环境中，基因表达的微阵列分析。使用PC-3异种移植小鼠模型来研究抑制LAT 1和LAT 3表达的作用。使用Mann-Whitney U或Fisher精确检验分析结果。结果LAT 3蛋白在前列腺癌各期均有表达，新辅助激素治疗4-7个月后表达明显下降（4-7个月平均值= 1.571; 95%置信区间= 1.155至1.987 vs 0个月= 2.098; 95%置信区间= 1.962至2.235; P = 0.0187）。LAT功能的抑制导致激活转录因子4介导的氨基酸转运蛋白（包括ASCT 1、ASCT 2和4F 2 hc）上调，所有这些转运蛋白也通过雄激素受体进行调节。LAT抑制抑制由E2 F家族转录因子调控的M期细胞周期基因，包括关键的去势抵抗性前列腺癌调控基因UBE 2C、CDC 20和CDK 1。BCH下调基因的计算机分析显示，在转移性去势抵抗性前列腺癌中，90.9%的基因在统计学上显著上调。最后，在异种移植物中的LAT 1或LAT 3敲低抑制肿瘤的生长，细胞周期的进展，并在vivo.Conclusion转移性去势抵抗性前列腺癌的LAT转运蛋白的抑制可能提供一个新的治疗靶点，通过抑制哺乳动物雷帕霉素复合物1的活性和M期细胞周期基因。
Background L-type amino acid transporters (LATs) uptake neutral amino acids including L-leucine into cells, stimulating mammalian target of rapamycin complex 1 signaling and protein synthesis. LAT1 and LAT3 are overexpressed at different stages of prostate cancer, and they are responsible for increasing nutrients and stimulating cell growth.Methods We examined LAT3 protein expression in human prostate cancer tissue microarrays. LAT function was inhibited using a leucine analog (BCH) in androgen-dependent and -independent environments, with gene expression analyzed by microarray. A PC-3 xenograft mouse model was used to study the effects of inhibiting LAT1 and LAT3 expression. Results were analyzed with the Mann-Whitney U or Fisher exact tests. All statistical tests were two-sided.Results LAT3 protein was expressed at all stages of prostate cancer, with a statistically significant decrease in expression after 4-7 months of neoadjuvant hormone therapy (4-7 month mean = 1.571; 95% confidence interval = 1.155 to 1.987 vs 0 month = 2.098; 95% confidence interval = 1.962 to 2.235; P = .0187). Inhibition of LAT function led to activating transcription factor 4-mediated upregulation of amino acid transporters including ASCT1, ASCT2, and 4F2hc, all of which were also regulated via the androgen receptor. LAT inhibition suppressed M-phase cell cycle genes regulated by E2F family transcription factors including critical castration-resistant prostate cancer regulatory genes UBE2C, CDC20, and CDK1. In silico analysis of BCH-downregulated genes showed that 90.9% are statistically significantly upregulated in metastatic castration-resistant prostate cancer. Finally, LAT1 or LAT3 knockdown in xenografts inhibited tumor growth, cell cycle progression, and spontaneous metastasis in vivo.Conclusion Inhibition of LAT transporters may provide a novel therapeutic target in metastatic castration-resistant prostate cancer, via suppression of mammalian target of rapamycin complex 1 activity and M-phase cell cycle genes.