Effects of tubastatin A on adrenocorticotropic hormone synthesis and proliferation of AtT-20 corticotroph tumor cells
Effects of tubastatin A on adrenocorticotropic hormone synthesis and proliferation of AtT-20 corticotroph tumor cells
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DOI：
10.1507/endocrj.ej21-0778
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发表时间：
2022-03-15
影响因子：
2
通讯作者：
Daimon, Makoto
中科院分区：
文献类型：
--
作者：
Hagiwara, Rie;Kageyama, Kazunori;Daimon, Makoto
库欣氏病是一种内分泌紊乱性疾病，其特征是皮质醇增多，主要由垂体腺瘤自主产生ACTH引起。自主ACTH分泌导致肾上腺皮质醇分泌过量，促肾上腺皮质激素腺瘤细胞破坏正常的皮质醇反馈机制。泛组蛋白去乙酰化酶（HDAC）抑制剂抑制AtT-20促肾上腺皮质激素肿瘤细胞中的细胞增殖和ACTH产生。已知选择性HDAC 6抑制剂发挥抗肿瘤作用并减少与抑制其他HDAC相关的不良反应。目前的研究表明，有效和选择性HDAC 6抑制剂tubastatin A对参与细胞增殖的前阿黑皮素（Pomc）和垂体肿瘤转化基因1（Pttg 1）mRNA表达具有抑制作用。tubastatin A处理后磷酸化Akt/Akt蛋白水平升高。因此，促肾上腺皮质激素细胞的增殖可能是通过Akt-Pttg 1途径调节的。地塞米松处理也降低了Pomc mRNA水平。联合tubastatin A和地塞米松治疗显示对Pomc mRNA水平的累加效应。因此，tubastatin A可用于治疗库欣病。
Cushing's disease is an endocrine disorder characterized by hypercortisolism, mainly caused by autonomous production of ACTH from pituitary adenomas. Autonomous ACTH secretion results in excess cortisol production from the adrenal glands, and corticotroph adenoma cells disrupt the normal cortisol feedback mechanism. Pan-histone deacetylase (HDAC) inhibitors inhibit cell proliferation and ACTH production in AtT-20 corticotroph tumor cells. A selective HDAC6 inhibitor has been known to exert antitumor effects and reduce adverse effects related to the inhibition of other HDACs. The current study demonstrated that the potent and selective HDAC6 inhibitor tubastatin A has inhibitory effects on proopiomelanocortin (Pomc) and pituitary tumor-transforming gene 1 (Pttg1) mRNA expression, involved in cell proliferation. The phosphorylated Akt/Akt protein levels were increased after treatment with tubastatin A. Therefore, the proliferation of corticotroph cells may be regulated through the Akt-Pttg1 pathway. Dexamethasone treatment also decreased the Pomc mRNA level. Combined tubastatin A and dexamethasone treatment showed additive effects on the Pomc mRNA level. Thus, tubastatin A may have applications in the treatment of Cushing's disease.