Division of Endocrinology and Metabolism, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada; Department of Biochemistry, Dokkyo Medical University School of Medicine, Mibu, Tochigi, Japan.
Division of Endocrinology and Metabolism, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
Mol Cell Endocrinol. 2020 Sep 15;515:110868. doi: 10.1016/j.mce.2020.110868. Epub 2020 Jun 21.
Pituitary tumors (PTs) can cause significant mortality and morbidity due to limited therapeutic options. L-type amino acid transporters (LATs), in particular, the LAT1 isoform, is expressed in a variety of tumor cells. Pharmacological inhibition or genetic ablation of LAT1 can suppress leucine transport into cancer cells, resulting in suppression of cancer cell growth. However, roles of LAT1 in PTs have not been elucidated. Therefore, we assessed LAT1 expression in PTs and evaluated a LAT1-specific inhibitor, JPH203, on rat somatomammotroph tumor cells, GH4 cells. GH4 cells dominantly express LAT1 mRNA rather than other LAT isoforms, whereas LAT2 transcripts were most abundant in normal rat pituitary tissues. JPH203 inhibited leucine uptake and cell growth in GH4 cells in a concentration-dependent manner, and appeared to be independent of the mechanistic target, the rapamycin pathway. Although JPH203 did not induce apoptosis, it suppressed growth hormone production in GH4 cells. Also, genetic downregulation of LAT1 showed similar effects on cell growth and hormone production. These results indicated that restriction of LAT1 substrates by JPH203 modulated both cell growth and hormone production. In conclusion, LAT1 may be a new therapeutic target for PTs because its inhibition leads to suppression of cell growth as well as hormone production. JPH203 may represent a promising drug for clinical use in patients with PTs, with the potential of hormonal control and tumor suppression.
垂体肿瘤 (PTs) 由于治疗选择有限，可能导致重大的死亡率和发病率。特别是 L 型氨基酸转运体 (LATs)，其 LAT1 同工型在各种肿瘤细胞中表达。LAT1 的药理学抑制或基因缺失可以抑制亮氨酸进入癌细胞，从而抑制癌细胞生长。然而，LAT1 在 PTs 中的作用尚未阐明。因此，我们评估了 PTs 中的 LAT1 表达，并评估了 LAT1 特异性抑制剂 JPH203 在大鼠生长激素分泌细胞瘤细胞 GH4 中的作用。GH4 细胞主要表达 LAT1 mRNA，而不是其他 LAT 同工型，而 LAT2 转录本在正常大鼠垂体组织中最为丰富。JPH203 以浓度依赖的方式抑制 GH4 细胞中的亮氨酸摄取和细胞生长，并且似乎与作用机制靶点雷帕霉素通路无关。尽管 JPH203 不会诱导细胞凋亡，但它抑制 GH4 细胞生长激素的产生。此外，LAT1 的基因下调对细胞生长和激素产生也表现出类似的作用。这些结果表明，JPH203 通过限制 LAT1 底物来调节细胞生长和激素产生。总之，LAT1 可能成为 PTs 的新治疗靶点，因为其抑制作用不仅可以抑制细胞生长，还可以抑制激素产生。JPH203 可能代表一种有前途的药物，可用于治疗 PTs 患者，具有激素控制和肿瘤抑制的潜力。
