Wei Ling, Tominaga Hideyuki, Ohgaki Ryuichi, Wiriyasermkul Pattama, Hagiwara Kohei, Okuda Suguru, Kaira Kyoichi, Oriuchi Noboru, Nagamori Shushi, Kanai Yoshikatsu
Department of Bio-system Pharmacology, Graduate School of Medicine, Osaka University, Suita, Japan.
Advanced Clinical Research Center, Fukushima Medical University, Fukushima, Japan.
Cancer Sci. 2016 Mar;107(3):347-52. doi: 10.1111/cas.12878. Epub 2016 Feb 19.
3-(18)F-l-α-methyl-tyrosine ([18F]FAMT), a PET probe for tumor imaging, has advantages of high cancer-specificity and lower physiologic background. FAMT-PET has been proved useful in clinical studies for the prediction of prognosis, the assessment of therapy response and the differentiation of malignant tumors from inflammation and benign lesions. The tumor uptake of [18F]FAMT in PET is strongly correlated with the expression of L-type amino acid transporter 1 (LAT1), an isoform of system L upregulated in cancers. In this study, to assess the transporter-mediated mechanisms in FAMT uptake by tumors, we examined amino acid transporters for FAMT transport. We synthesized [14C]FAMT and measured its transport by human amino acid transporters expressed in Xenopus oocytes. The transport of FAMT was compared with that of l-methionine, a well-studied amino acid PET probe. The significance of LAT1 in FAMT uptake by tumor cells was confirmed by siRNA knockdown. Among amino acid transporters, [14C]FAMT was specifically transported by LAT1, whereas l-[14C]methionine was taken up by most of the transporters. Km of LAT1-mediated [14C]FAMT transport was 72.7 μM, similar to that for endogenous substrates. Knockdown of LAT1 resulted in the marked reduction of [14C]FAMT transport in HeLa S3 cells, confirming the contribution of LAT1 in FAMT uptake by tumor cells. FAMT is highly specific to cancer-type amino acid transporter LAT1, which explains the cancer-specific accumulation of [18F]FAMT in PET. This, vice versa, further supports the cancer-specific expression of LAT1. This study has established FAMT as a LAT1-specific molecular probe to monitor the expression of a potential tumor biomarker LAT1.
3-(18)F-l-α-甲基酪氨酸（[18F]FAMT）是一种用于肿瘤成像的正电子发射断层显像（PET）探针，具有高癌症特异性和较低生理本底的优点。FAMT-PET已在临床研究中被证明可用于预测预后、评估治疗反应以及区分恶性肿瘤与炎症和良性病变。PET中[18F]FAMT的肿瘤摄取与L型氨基酸转运体1（LAT1）的表达密切相关，LAT1是在癌症中上调的L系统的一种亚型。在本研究中，为了评估肿瘤摄取FAMT的转运体介导机制，我们检测了转运FAMT的氨基酸转运体。我们合成了[14C]FAMT，并测量了其在非洲爪蟾卵母细胞中表达的人类氨基酸转运体介导的转运。将FAMT的转运与l-甲硫氨酸（一种研究充分的氨基酸PET探针）的转运进行了比较。通过小干扰RNA（siRNA）敲低证实了LAT1在肿瘤细胞摄取FAMT中的重要性。在氨基酸转运体中，[14C]FAMT由LAT1特异性转运，而l-[14C]甲硫氨酸被大多数转运体摄取。LAT1介导的[14C]FAMT转运的米氏常数（Km）为72.7μM，与内源性底物相似。敲低LAT1导致HeLa S3细胞中[14C]FAMT转运显著减少，证实了LAT1在肿瘤细胞摄取FAMT中的作用。FAMT对癌症类型的氨基酸转运体LAT1具有高度特异性，这解释了PET中[18F]FAMT的癌症特异性积聚。反之，这进一步支持了LAT1的癌症特异性表达。本研究已将FAMT确立为一种LAT1特异性分子探针，用于监测潜在肿瘤生物标志物LAT1的表达。
