Department of Obstetrics and Gynecology, Kyorin University School of Medicine, Mitaka, Tokyo, Japan.
Int J Gynecol Cancer. 2010 Apr;20(3):329-36. doi: 10.1111/IGC.0b013e3181d28e13.
To investigate the expression and the functional properties of L-type amino acid transporter 1 (LAT1) in human epithelial ovarian cancer to provide a basis for potential new therapies to control the growth and the metastasis of ovarian cancer.
The material used comprised 63 surgically resected specimens obtained from female patients undergoing gynecologic surgery at Kyorin University School of Medicine (Tokyo, Japan). The expression of LAT1 in 53 cases of ovarian cancers was determined by Western blot and immunohistochemical staining, and results were compared with those of normal ovarian tissues (5 cases) and benign ovarian tumors (5 cases). Furthermore, we examined the effect of 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH), the classic inhibitor of system L on the survival, the migration, and the uptake of l-leucine by human epithelial ovarian cancer cell line (OVCAR-3).
The LAT1 was significantly up-regulated in various human epithelial ovarian cancers that was localized predominantly on their plasma membrane and in the plasma membrane of the ovarian cancer cell line in conjunction with 4F2hc via disulfide bonds. The BCH inhibited the proliferation and the migration of the OVCAR-3 cells and the uptake of [14C]l-leucine by these cells in a dose-dependent manner. The OVCAR-3 cells did not express LAT2, and the uptake of [14C]l-leucine by these cells was Na-independent and almost completely inhibited by BCH. Thus, our findings indicated that most l-leucine uptake in OVCAR-3 cells was mediated by LAT1.
The LAT1 plays significant roles in nutrition, proliferation, and migration of ovarian cancer. Then, LAT1 inhibition would be useful for anticancer therapy in suppressing tumor growth without affecting normal tissues.
研究 L 型氨基酸转运蛋白 1（LAT1）在人上皮性卵巢癌中的表达和功能特性，为控制卵巢癌生长和转移的潜在新疗法提供依据。
本研究使用的材料包括 63 例来自在日本庆应义塾大学医学院接受妇科手术的女性患者的手术切除标本。通过 Western blot 和免疫组织化学染色测定 53 例卵巢癌中 LAT1 的表达，并将结果与 5 例正常卵巢组织和 5 例良性卵巢肿瘤进行比较。此外，我们还研究了 2-氨基二环[2.2.1]庚烷-2-羧酸（BCH），即系统 L 的经典抑制剂对人上皮性卵巢癌细胞系（OVCAR-3）生存、迁移和 l-亮氨酸摄取的影响。
LAT1 在各种人上皮性卵巢癌中明显上调，主要定位于其质膜上，并与 4F2hc 通过二硫键结合存在于卵巢癌细胞系的质膜上。BCH 以剂量依赖性方式抑制 OVCAR-3 细胞的增殖和迁移，以及这些细胞对[14C]l-亮氨酸的摄取。OVCAR-3 细胞不表达 LAT2，这些细胞对[14C]l-亮氨酸的摄取是钠离子非依赖性的，并且几乎完全被 BCH 抑制。因此，我们的研究结果表明，OVCAR-3 细胞中大多数 l-亮氨酸摄取是由 LAT1 介导的。
LAT1 在卵巢癌的营养、增殖和迁移中发挥重要作用。因此，抑制 LAT1 可能有助于抗癌治疗，在抑制肿瘤生长的同时不影响正常组织。
