Inhibitory effects of trichostatin A on adrenocorticotropic hormone production and proliferation of corticotroph tumor AtT-20 cells
Inhibitory effects of trichostatin A on adrenocorticotropic hormone production and proliferation of corticotroph tumor AtT-20 cells
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DOI：
10.1507/endocrj.ej15-0369
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发表时间：
2015-12-20
影响因子：
2
通讯作者：
Daimon, Makoto
中科院分区：
文献类型：
--
作者：
Nakada, Yuki;Kageyama, Kazunori;Daimon, Makoto
库欣病主要由产生促肾上腺皮质激素（ACTH）的垂体腺瘤引起。垂体肿瘤转化基因 1 (PTTG1) 的表达是垂体肿瘤的标志，可刺激垂体细胞增殖。组蛋白脱乙酰酶 (HDAC) 在调节基因转录中发挥重要作用，HDAC 抑制剂可诱导细胞分化并抑制肿瘤细胞增殖。 HDAC 抑制剂还抑制 PTTG1 mRNA 水平。 Trichostatin A (TSA) 是一种有效的细胞渗透性 HDAC 抑制剂，可阻断细胞周期进程。在本研究中，我们确定了 TSA 对小鼠 AtT-20 促肾上腺皮质激素肿瘤细胞中 ACTH 产生和细胞增殖的影响。 TSA 降低 AtT-20 细胞中阿片黑皮质素原 (POMC) mRNA 水平，并降低这些细胞培养基中的 ACTH 水平。当同时给予 TSA 和地塞米松时，TSA 诱导的 POMC mRNA 水平降低并未受到调节。药物治疗还减少了 AtT-20 细胞增殖，诱导细胞凋亡，并通过流式细胞术增加了 G0/G1 期细胞的百分比。 TSA 降低了 PTTG1 mRNA 水平。此外，PTTG1 敲低抑制细胞增殖。它的敲低还抑制了 POMC mRNA 和 ACTH 水平。 TSA 抑制 ACTH 产生和促肾上腺皮质激素肿瘤细胞增殖。 TSA 可能通过降低 PTTG1 表达来抑制细胞增殖以及 ACTH 合成和分泌。
Cushing's disease is primarily caused by adrenocorticotropic hormone (ACTH)-producing pituitary adenomas. Pituitary tumor-transforming gene 1 (PTTG1) expression, a hallmark of pituitary tumors, stimulates pituitary cell proliferation. Histone deacetylases (HDACs) play an important role in regulating gene transcription and HDAC inhibitors induce cellular differentiation and suppress tumor cell proliferation. HDAC inhibitors also repress PTTG1 mRNA levels. Trichostatin A (TSA) is a potent cell-permeable HDAC inhibitor that blocks cell cycle progression. In the present study, we determined the effect of TSA on ACTH production and cellular proliferation in mouse AtT-20 corticotroph tumor cells. TSA decreased proopiomelanocortin (POMC) mRNA levels in AtT-20 cells and reduced ACTH levels in the culture medium of these cells. The TSA-induced decreases in POMC mRNA levels were not modulated when TSA and dexamethasone were simultaneously administered. Drug treatment also decreased AtT-20 cell proliferation, induced apoptosis, and increased the percentage of cells in G0/G1 phase using flow cytometry. TSA decreased PTTG1 mRNA levels. Furthermore, PTTG1 knockdown inhibited cellular proliferation. Its knockdown also inhibited POMC mRNA and ACTH levels. TSA inhibits ACTH production and corticotroph tumor cell proliferation. TSA may inhibit cellular proliferation, and ACTH synthesis and secretion by decreasing PTTG1 expression.