A new treatment for human malignant melanoma targeting L-type amino acid transporter 1 (LAT1): A pilot study in a canine model
A new treatment for human malignant melanoma targeting L-type amino acid transporter 1 (LAT1): A pilot study in a canine model
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DOI：
10.1016/j.bbrc.2013.08.020
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发表时间：
2013-09-13
影响因子：
3.1
通讯作者：
Uchide, Tsuyoshi
中科院分区：
文献类型：
--
作者：
Fukumoto, Shinya;Hanazono, Kiwamu;Uchide, Tsuyoshi
L型氨基酸转运蛋白1（LAT 1）是氨基酸转运系统L的一种亚型，主要转运细胞生长、增殖和维持等基本细胞活动所必需的支链或芳香族氨基酸。这种氨基酸转运蛋白最近受到关注，因为它在各种人类肿瘤中的优先和上调表达，而不是其在正常组织中的有限分布和低水平表达。在这项研究中，我们探索了使用LAT 1抑制剂作为人类恶性黑色素瘤（MM）的新治疗剂的可行性，使用犬自发性MM作为人类MM的模型。在48个正常组织中进行了LAT表达的比较研究，该研究观察到来自MM组织和细胞系的LAT 1 mRNA水平显著高于来自MM组织和细胞系的LAT 1 mRNA水平。（P < 0.01）高于正常组织。有远处转移的MM患者的表达高于无远处转移的MM患者。在五种细胞系之一CMeC-1上进行LAT 1的功能分析。选择性LAT 1抑制剂（2-氨基-2-降冰片烷-羧酸，BCH和美法仑，LPM）以剂量依赖性方式抑制CMec-1中的[H-3] L-亮氨酸摄取和细胞生长活性。BCH或LPM与卡铂、环磷酰胺、达卡巴嗪、多柔比星、米托蒽醌、尼莫司汀、长春碱和长春新碱联合使用时，其抑制肿瘤生长的活性均显著增强（P < 0.05）。这些发现表明，LAT 1可能是MM的新治疗靶点。（C）2013 Elsevier Inc. All rights reserved.
L-type amino acid transporter 1 (LAT1), an isoform of amino acid transport system L, transports branched or aromatic amino acids essential for fundamental cellular activities such as cellular growth, proliferation and maintenance. This amino acid transporter recently has received attention because of its preferential and up-regulated expression in a variety of human tumors in contrast to its limited distribution and low-level expression in normal tissues. In this study, we explored the feasibility of using LAT1 inhibitor as a new therapeutic agent for human malignant melanomas (MM) using canine spontaneous MM as a model for human MM. A comparative study of LAT expression was performed in 48 normal tissues, 25 MM tissues and five cell lines established from MM. The study observed LAT1 mRNA levels from MM tissues and cell lines that were significantly (P < 0.01) higher than in normal tissues. Additionally, MM with distant metastasis showed a higher expression than those without distant metastasis. Functional analysis of LAT1 was performed on one of the five cell lines, CMeC-1. [H-3]L-Leucine uptake and cellular growth activities in CMeC-1 were inhibited in a dose-dependent manner by selective LAT1 inhibitors (2-amino-2-norbornane-carboxylic acid, BCH and melphalan, LPM). Inhibitory growth activities of various conventional anti-cancer drugs, including carboplatin, cyclophosphamide, dacarbazine, doxorubicin, mitoxantrone, nimustine, vinblastine and vincristine, were significantly (P < 0.05) enhanced by combination use with BCH or LPM. These findings suggest that LAT1 could be a new therapeutic target for MM. (C) 2013 Elsevier Inc. All rights reserved.