L-type amino acid transporter 1, LAT1, in growth hormone-producing pituitary tumor cells
L-type amino acid transporter 1, LAT1, in growth hormone-producing pituitary tumor cells
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DOI：
10.1016/j.mce.2020.110868
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发表时间：
2020-09-15
影响因子：
4.1
通讯作者：
Tateno, Toru
中科院分区：
文献类型：
--
作者：
Satou, Motoyasu;Wang, Jason;Tateno, Toru
由于有限的治疗选择，胰腺癌（PT）可导致显著的死亡率和发病率。L型氨基酸转运蛋白（LAT），特别是LAT1亚型，在多种肿瘤细胞中表达。LAT1的药理学抑制或基因消融可以抑制亮氨酸转运到癌细胞中，从而抑制癌细胞生长。然而，LAT1在PT中的作用尚未阐明。因此，我们评估了PT中的LAT1表达，并评估了大鼠生长激素促乳细胞瘤细胞GH4细胞上的LAT1特异性抑制剂JPH 203。GH4细胞主要表达LAT1 mRNA，而不是其他LAT亚型，而LAT2转录本在正常大鼠垂体组织中最丰富。JPH 203以浓度依赖性方式抑制GH4细胞中亮氨酸摄取和细胞生长，并且似乎不依赖于机制靶点雷帕霉素途径。虽然JPH 203不诱导细胞凋亡，但它抑制了GH 4细胞生长激素的产生。此外，LAT1的遗传下调对细胞生长和激素产生也有类似的影响。这些结果表明，通过JPH 203限制LAT1底物调节细胞生长和激素产生。总之，LAT1可能是PT的一个新的治疗靶点，因为它的抑制导致细胞生长和激素产生的抑制。JPH 203可能是一种有前途的药物，可用于PT患者的临床治疗，具有激素控制和肿瘤抑制的潜力。
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.