Specific transport of 3-fluoro-l-α-methyl-tyrosine by LAT1 explains its specificity to malignant tumors in imaging.
Specific transport of 3-fluoro-l-α-methyl-tyrosine by LAT1 explains its specificity to malignant tumors in imaging.
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DOI：
10.1111/cas.12878
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发表时间：
2016-03
期刊：
影响因子：
5.7
通讯作者：
Kanai Y
中科院分区：
文献类型：
--
作者：
Wei L;Tominaga H;Ohgaki R;Wiriyasermkul P;Hagiwara K;Okuda S;Kaira K;Oriuchi N;Nagamori S;Kanai Y
3‐18F‐1‐α‐甲基酪氨酸（[18F]FAMT）是一种用于肿瘤成像的PET探针，具有高肿瘤特异性和低生理背景的优点。在临床研究中，FAMT‐PET已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型氨基酸转运蛋白1 （LAT1）的表达密切相关，LAT1是L系统在癌症中上调的同型异构体。在本研究中，为了评估转运蛋白介导的肿瘤摄取FAMT的机制，我们研究了FAMT转运的氨基酸转运蛋白。我们合成了[14C]FAMT，并测定了其在爪蟾卵母细胞中表达的人氨基酸转运蛋白的转运情况。FAMT的转运与l -蛋氨酸的转运进行了比较，l -蛋氨酸是一种研究得很好的氨基酸PET探针。通过敲低siRNA证实了LAT1在肿瘤细胞摄取FAMT中的意义。在氨基酸转运体中，[14C]FAMT被LAT1特异转运，而l‐[14C]蛋氨酸被大多数转运体吸收。LAT1‐介导的[14C] fam转运Km为72.7 μM，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对癌症型氨基酸转运蛋白LAT1具有高度特异性，这解释了[18F]FAMT在PET中的癌症特异性积累。反之亦然，这进一步支持了LAT1的癌症特异性表达。本研究建立了FAMT作为LAT1特异性分子探针来监测潜在肿瘤生物标志物LAT1的表达。
3‐18F‐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.