选择性抑制 L 型氨基酸转运蛋白 1 可抑制卵巢透明细胞癌的细胞增殖。

Selective Inhibition of L-type Amino Acid Transporter 1 Suppresses Cell Proliferation in Ovarian Clear Cell Carcinoma.

机构信息

Department of Obstetrics and Gynecology, Faculty of Medicine Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.

Department of Obstetrics and Gynecology, Faculty of Medicine Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan

出版信息

Anticancer Res. 2023 Jun;43(6):2509-2517. doi: 10.21873/anticanres.16418.

DOI:10.21873/anticanres.16418

PMID:37247931

Abstract

BACKGROUND/AIM: Ovarian clear cell carcinoma (OCCC) is a histological type of ovarian cancer that is refractory to chemotherapy and has poor prognosis, which necessitates the development of novel treatment therapies. In this study, we focused on L-type amino acid transporter 1 (LAT1), which is involved in cancer growth, and investigated the effect of its selective inhibition on cell proliferation in OCCC.

MATERIALS AND METHODS

The inhibitory effect of nanvuranlat (JPH203), a LAT1 selective inhibitor, on the cellular uptake of [H] leucine was evaluated using the OCCC cell line JHOC9, which expresses the LAT1 protein. In addition, the kinetics of cell proliferation and changes in phosphorylation of the mTOR pathway were analyzed. The correlation between LAT1 expression and progression-free survival (PFS) was evaluated using clinical specimens of OCCC.

RESULTS

Nanvuranlat inhibited [H] leucine intracellular uptake and cell proliferation in a dose-dependent manner in JHOC9 cells. In addition, it suppressed the activity of the mTOR signaling pathway, which is thought to inhibit cancer cell proliferation. LAT1 expression was most frequent in OCCC among clinical specimens of epithelial ovarian cancer. A correlation between LAT1 expression and PFS was observed in OCCC.

CONCLUSION

LAT1 selective inhibition suppresses cell proliferation via the mTOR pathway by inhibiting leucine uptake in OCCC. This study illustrates the potential of using LAT1 selective inhibition as a treatment strategy for OCCC.

摘要

背景/目的：卵巢透明细胞癌（OCCC）是一种对化疗耐药且预后不良的卵巢癌组织学类型，这就需要开发新的治疗方法。在这项研究中，我们专注于 L 型氨基酸转运蛋白 1（LAT1），它与肿瘤生长有关，并研究了其选择性抑制对 OCCC 细胞增殖的影响。

材料和方法

使用表达 LAT1 蛋白的 OCCC 细胞系 JHOC9 评估 LAT1 选择性抑制剂 nanvuranlat（JPH203）对 [H]亮氨酸细胞摄取的抑制作用。此外，还分析了细胞增殖的动力学和 mTOR 通路磷酸化的变化。使用 OCCC 的临床标本评估了 LAT1 表达与无进展生存期（PFS）之间的相关性。

结果

nanvuranlat 以剂量依赖的方式抑制 JHOC9 细胞中 [H]亮氨酸的细胞内摄取和细胞增殖。此外，它抑制了 mTOR 信号通路的活性，这被认为可以抑制癌细胞的增殖。LAT1 表达在卵巢上皮性癌的临床标本中在 OCCC 中最为常见。在 OCCC 中观察到 LAT1 表达与 PFS 之间存在相关性。