Ubiquitin-specific protease 8 inhibitor suppresses adrenocorticotropic hormone production and corticotroph tumor cell proliferation
Ubiquitin-specific protease 8 inhibitor suppresses adrenocorticotropic hormone production and corticotroph tumor cell proliferation
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DOI：
10.1507/endocrj.ej19-0239
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发表时间：
2020-01-01
影响因子：
2
通讯作者：
Daimon, Makoto
中科院分区：
文献类型：
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作者：
Kageyama, Kazunori;Asari, Yuko;Daimon, Makoto
库欣氏病主要由垂体腺瘤的促肾上腺皮质激素（ACTH）自主分泌过多引起。在库欣病中，已检测到泛素特异性蛋白酶8（USP 8）的突变。这些突变与防止表皮生长因子受体（EGFR）降解的USP 8超活化相关。这导致EGFR稳定性增加并导致库欣病中EGFR信号传导的维持。USP 8抑制剂可以抑制各种肿瘤的生长。在这项研究中，一种有效的USP 8抑制剂DUBs-IN-2对小鼠促肾上腺皮质激素肿瘤（AtT.20）细胞中ACTH产生和细胞增殖的影响进行了研究。DUBS-IN-2可降低AtT-20细胞中阿黑皮素原（Pomc）mRNA水平和ACTH水平。此外，DUBs-IN-2可抑制细胞增殖并诱导细胞凋亡。垂体肿瘤转化基因1（Pttg 1）（一种垂体肿瘤生长标志物）的转录水平增加;应激反应生长停滞和DNA损伤诱导型45（Gadd 45 β）的转录水平以及Cdk 5和ABL酶底物1（Cables 1）mRNA水平在对药物的反应中增加。Gadd 45 β或Cables 1敲低部分抑制DUB s-IN-2诱导的细胞增殖降低，但不抑制Pomc mRNA水平。GADD 45 β和CABLES 1可能至少部分地负责USP 8诱导的促肾上腺皮质激素肿瘤细胞增殖的抑制。USP-8可能成为治疗库欣病的新靶点。
Cushing's disease is primarily caused by autonomic hypersecretion of adrenocorticotropic hormone (ACTH) from a pituitary adenoma. In Cushing's disease, mutations in the ubiquitin-specific protease 8 (USP8) have been detected. These mutations are associated with hyperactivation of USP8 that prevent epidermal growth factor receptor (EGFR) degradation. This leads to increased EGFR stability and results in the maintenance of EGFR signaling in Cushing's disease. USP8 inhibitors can suppress the growth of various tumors. In this study, the effects of a potent USP8 inhibitor, DUBs-IN-2, on ACTH production and cell proliferation were examined in mouse corticotroph tumor (AtT.20) cells. Proopiomelanocortin (Pomc) mRNA levels and ACTH levels were decreased in AtT-20 cells by DUBS-IN-2. Further, cell proliferation was inhibited, and apoptosis was induced by DUBs-IN-2. Transcript levels of pituitary tumor-transforming gene 1 (Pttg1), a pituitary tumor growth marker, were increased; and transcript levels of stress response growth arrest and DNA damage-inducible 45 (Gadd45 beta) and Cdk5 and ABL enzyme substrate 1 (Cables1) mRNA levels were increased in response to the drug. Gadd45 beta or Cables1 knockdown partially inhibited the DUB s-IN-2-induced decrease in cell proliferation, but not Pomc mRNA levels. Both GADD45 beta and CABLES1 may be responsible, at least in part, for the USP8-induced suppression of corticotroph tumor cell proliferation. USP-8 may be a new treatment target in Cushing's disease.