Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka, 819-0395, Japan.
Department of Chemical Science and Engineering, Tokyo Institute of Technology, 2-12-1 Ookayama, Meguro, Tokyo, 152-8552, Japan.
Biochem Biophys Res Commun. 2020 May 14;525(4):974-981. doi: 10.1016/j.bbrc.2020.03.021. Epub 2020 Mar 12.
Targeting proteins that are overexpressed in cancer cells is the major strategy of molecular imaging and drug delivery systems. The 67-kDa laminin receptor (67LR), also known as oncofetal antigen, is overexpressed in several types of cancer, including melanoma, multiple myeloma, cervical cancer and bile duct carcinoma. 67LR is involved in tumour growth, tumour metastasis and drug resistance. Green tea polyphenol (-)-epigallocatechin-3-O-gallate (EGCG) directly binds to cell-surface 67LR and induces apoptosis through the protein kinase B (Akt)/endothelial nitric oxide synthase/nitric oxide/cyclic GMP (cGMP) axis. Here we report the optimum hydroxyl group for the utilization of EGCG as a novel fluorescent EGCG-mimic imaging probe based on 67LR agonist characters, including Akt activation and inhibitory effect on viable cell number in cancer cells. 67LR specific targeting is unambiguously confirmed with the use of a non-labelled EGCG competitive assay and 67LR knockdown. Importantly, this probe strongly binds to multiple myeloma cells compared with its binding to normal cells.
靶向在癌细胞中过度表达的蛋白质是分子成像和药物输送系统的主要策略。67kDa 层粘连蛋白受体（67LR），也称为癌胚抗原，在多种癌症中过度表达，包括黑色素瘤、多发性骨髓瘤、宫颈癌和胆管癌。67LR 参与肿瘤生长、肿瘤转移和耐药性。绿茶多酚（-）-表没食子儿茶素-3-O-没食子酸酯（EGCG）直接与细胞表面的 67LR 结合，并通过蛋白激酶 B（Akt）/内皮型一氧化氮合酶/一氧化氮/环鸟苷酸（cGMP）轴诱导细胞凋亡。在这里，我们根据 67LR 激动剂的特性，报告了 EGCG 作为新型荧光 EGCG 模拟成像探针的最佳羟基利用情况，包括 Akt 激活和对癌细胞活力的抑制作用。使用非标记的 EGCG 竞争测定和 67LR 敲低，明确证实了 67LR 的特异性靶向。重要的是，与正常细胞相比，该探针与多发性骨髓瘤细胞强烈结合。
