System L amino acid transporter inhibitor enhances anti-tumor activity of cisplatin in a head and neck squamous cell carcinoma cell line
System L amino acid transporter inhibitor enhances anti-tumor activity of cisplatin in a head and neck squamous cell carcinoma cell line
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DOI：
10.1016/j.canlet.2008.10.035
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发表时间：
2009-04-08
期刊：
影响因子：
9.7
通讯作者：
Kohno, Naoyuki
中科院分区：
文献类型：
--
作者：
Yamauchi, Kohichi;Sakurai, Hiroyuki;Kohno, Naoyuki
LAT1是异二聚体系统L转运蛋白的一个亚单位，负责将中性氨基酸输送到细胞内，由于其具有癌胎儿性质，已在几种癌症中得到研究。基于对其功能抑制的研究，LAT1已被认为是治疗癌症的一个新的分子靶点。我们在这里已经证明，人头颈部癌细胞株HEP-2同时表达LAT1和4F2hc，这是系统L转运蛋白的另一个亚单位。L系统的抑制剂2-氨基双环-(2，2，1)-庚烷-2-羧酸(BCH)可抑制细胞摄取亮氨酸。BCH处理或限制必需氨基酸亮氨酸可降低Hep-2细胞的存活率。与单独给药相比，顺铂和BCH联合给药对细胞活力的影响更大。当BCH治疗先于顺铂给药时，Hep-2细胞活力的降低是相加的。相反，当BCH在顺铂治疗后给予时。在减少活细胞数方面取得了协同效应。BCH使mTOR、p70S6K和4EBP1的磷酸化水平降低，提示BCH通过抑制mTOR通路增强顺铂的抗肿瘤作用。这种增强作用可用于减少顺铂的暴露，以减轻该药物的许多有害毒性。(C)2008爱思唯尔爱尔兰有限公司。保留所有权利。
LAT1, a subunit of heterodimeric system L transporter responsible for transporting neutral amino acids into cells, has been investigated in several cancers because of its onco-fetal nature. Based on the studies of its functional inhibition, LAT1 has been proposed to be a new molecular target of a cancer therapy. We have shown here that human head and neck cancer cell line, Hep-2, expresses both LAT1 and 4F2hc, another subunit of system L transporter. An inhibitor of system L, 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH), inhibited leucine uptake by the cells. BCH administration or restriction of essential amino acid leucine decreased viability of Hep-2 cells. Co-administration of cisplatin with BCH reduced the viability of the cells more than either agent alone. When BCH treatment preceded cisplatin administration, reduction in Hep-2 cell viability was additive. In contrast, when BCH was given after cisplatin treatment. synergistic effect in decreasing the number of viable cells was obtained. BCH treatment decreased the phosphorylation of mTOR, p70S6K and 4EBP1, suggesting that BCH enhanced anti-tumor action of cisplatin by inhibiting mTOR pathway. This potentiation may be used to reduce cisplatin exposure to alleviate many unwanted toxicity of the drug. (C) 2008 Elsevier Ireland Ltd. All rights reserved.