Amino acid transporter SLC6A14 is a novel and effective drug target for pancreatic cancer
Amino acid transporter SLC6A14 is a novel and effective drug target for pancreatic cancer
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DOI：
10.1111/bph.13616
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发表时间：
2016-12-01
影响因子：
7.3
通讯作者：
Bhutia, Y. D.
中科院分区：
文献类型：
--
作者：
Coothankandaswamy, V.;Cao, S.;Bhutia, Y. D.
背景和目的胰腺癌是一种致命的实体肿瘤。因此，迫切需要为这种疾病确定新的药物靶点。高度增殖的癌细胞对营养素的需求增加，因此需要上调选择性氨基酸转运蛋白。在这里，我们调查了哪些氨基酸转运蛋白在胰腺癌中上调，以及这些转运蛋白中是否有任何一种具有作为药物靶点的潜力，这种致命的diseases.Experimental ApproachThe表达的氨基酸转运蛋白在胰腺癌中进行了分析，使用公开的微阵列数据集，并与转运蛋白SLC 6A 14的研究结果进行了验证的mRNA和蛋白质分析。SLC 6A 14作为药物靶点的潜力进行了评估，使用药理学阻滞剂在体外和在vivo.Key ResultsSLC 6A 14上调几倍，在患者来源的异种移植物，原发性肿瘤组织和胰腺癌细胞系相比，正常胰腺组织或正常胰腺上皮细胞。SLC 6A 14的上调幅度在所检查的氨基酸转运蛋白中最高。SLC 6A 14的药理学阻断剂-甲基色氨酸可诱导胰腺癌细胞的氨基酸饥饿并降低这些细胞的生长和增殖，结论与意义本研究的显著特点是SLC 6A 14显著上调，在胰腺癌中受到调节，并且这种转运蛋白的药理学阻断会干扰氨基酸营养并减少胰腺癌的生长和增殖。胰腺癌细胞这些发现将SLC 6A 14确定为胰腺癌的新药物靶点。
Background and PurposePancreatic cancer is a solid tumour that is often fatal. Hence, there is an urgent need to identify new drug targets for this disease. Highly proliferating cancer cells have an increased demand for nutrients and, therefore, need to up-regulate selective amino acid transporters. Here, we investigated which amino acid transporters are up-regulated in pancreatic cancer and whether any of these transporters has potential as a drug target for this fatal disease.Experimental ApproachThe expression of amino acid transporters in pancreatic cancer was analysed using publicly available microarray datasets, and the findings with the transporter SLC6A14 were validated by mRNA and protein analysis. The potential of SLC6A14 as a drug target was evaluated using a pharmacological blocker in vitro and in vivo.Key ResultsSLC6A14 was up-regulated several fold in patient-derived xenografts, primary tumour tissues and pancreatic cancer cells lines compared to normal pancreatic tissue or normal pancreatic epithelial cells. The magnitude of the up-regulation of SLC6A14 was the highest among the amino acid transporters examined. A pharmacological blocker of SLC6A14, -methyltryptophan, induced amino acid starvation in pancreatic cancer cells and reduced the growth and proliferation of these cells, both in vitro and in vivo.Conclusion and ImplicationsThe salient features of this study are that SLC6A14 is markedly up-regulated in pancreatic cancer and that pharmacological blockade of this transporter interferes with amino acid nutrition and reduces growth and proliferation of pancreatic cancer cells. These findings identify SLC6A14 as a novel druggable target for pancreatic cancer.