Efficacy of system l amino acid transporter 1 inhibition as a therapeutic target in esophageal squamous cell carcinoma.
Efficacy of system l amino acid transporter 1 inhibition as a therapeutic target in esophageal squamous cell carcinoma.
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DOI：
10.1111/cas.13021
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发表时间：
2016-10
期刊：
影响因子：
5.7
通讯作者：
Ishioka NS
中科院分区：
文献类型：
--
作者：
Ohshima Y;Kaira K;Yamaguchi A;Oriuchi N;Tominaga H;Nagamori S;Kanai Y;Yokobori T;Miyazaki T;Asao T;Tsushima Y;Kuwano H;Ishioka NS
系统1氨基酸转运蛋白1（LAT 1）在各种类型的人类癌症中高度表达，并且有助于癌症生长和存活。最近，我们发现LAT 1的表达与食管癌的生长和侵袭性密切相关，并且是预后不良的独立标志物。然而，目前尚不清楚LAT 1抑制是否可以抑制食管癌的生长。在这项研究中，我们研究了抑制LAT 1的肿瘤抑制作用。LAT 1和与LAT 1在膜上共价结合的CD 98在人食管癌细胞系KYSE 30和KYSE 150中表达。定量PCR分析显示，LAT 1的表达明显高于其他LAT亚型。LAT的选择性抑制剂2-氨基双环-（2，2，1）-庚烷-2-羧酸（BCH）以剂量依赖性方式抑制细胞摄取1 - 14 C-亮氨酸和细胞增殖。它还抑制哺乳动物雷帕霉素靶蛋白、4 E-BP 1和p70 S6 K蛋白的磷酸化，并诱导细胞周期停滞在G1期。这些结果表明，抑制哺乳动物雷帕霉素靶信号和细胞周期进程参与BCH诱导的生长抑制。在荷瘤小鼠中，每日用BCH治疗显著延迟肿瘤生长并降低葡萄糖代谢，表明LAT 1抑制可能抑制体内食管癌生长。因此，我们的研究结果表明，LAT 1抑制可能是食管癌治疗的一个有前途的分子靶点。
System l amino acid transporter 1 (LAT1) is highly expressed in various types of human cancer, and contributes to cancer growth and survival. Recently, we have shown that LAT1 expression is closely related to the growth and aggressiveness of esophageal cancer, and is an independent marker of poor prognosis. However, it remains unclear whether LAT1 inhibition could suppress esophageal cancer growth. In this study, we investigated the tumor‐suppressive effects of the inhibition of LAT1. Both LAT1 and CD98, which covalently associates to LAT1 on the membrane, were expressed in human esophageal cancer cell lines KYSE30 and KYSE150. Quantitative PCR analysis showed that the expression of LAT1 was much higher than other subtypes of LAT. A selective inhibitor of LAT, 2‐aminobicyclo‐(2,2,1)‐heptane‐2‐carboxylic acid (BCH), suppressed cellular uptake of l‐14C‐leucine and cell proliferation in a dose‐dependent manner. It also suppressed phosphorylation of mammalian target of rapamycin, 4E‐BP1, and p70S6K protein, and induced cell cycle arrest at G1 phase. These results suggest that suppression of both mammalian target of rapamycin signaling and cell cycle progression is involved in BCH‐induced growth inhibition. In tumor‐bearing mice, daily treatment with BCH significantly delayed tumor growth and decreased glucose metabolism, indicating that LAT1 inhibition potentially suppresses esophageal cancer growth in vivo. Thus, our results suggest that LAT1 inhibition could be a promising molecular target for the esophageal cancer therapy.
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影响因子：
3.5
作者：
Khunweeraphong N;Nagamori S;Wiriyasermkul P;Nishinaka Y;Wongthai P;Ohgaki R;Tanaka H;Tominaga H;Sakurai H;Kanai Y
通讯作者：
Kanai Y
影响因子：
8.8
作者：
Kaira, K.;Oriuchi, N.;Imai, H.;Shimizu, K.;Yanagitani, N.;Sunaga, N.;Hisada, T.;Tanaka, S.;Ishizuka, T.;Kanai, Y.;Endou, H.;Nakajima, T.;Mori, M.
通讯作者：
Mori, M.
影响因子：
5.7
作者：
Oda, Koji;Hosoda, Noriko;Endou, Hitoshi
通讯作者：
Endou, Hitoshi
DOI：
10.1016/j.bbrc.2013.08.020
发表时间：
2013-09-13
影响因子：
3.1
作者：
Fukumoto, Shinya;Hanazono, Kiwamu;Uchide, Tsuyoshi
通讯作者：
Uchide, Tsuyoshi
影响因子：
13.3
作者：
Saiki, Shinji;Sasazawa, Yukiko;Hattori, Nobutaka
通讯作者：
Hattori, Nobutaka