Triptolide suppresses growth and hormone secretion in murine pituitary corticotroph tumor cells via NF-kappaB signaling pathway
Triptolide suppresses growth and hormone secretion in murine pituitary corticotroph tumor cells via NF-kappaB signaling pathway
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DOI：
10.1016/j.biopha.2017.08.127
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发表时间：
2017-11-01
影响因子：
7.5
通讯作者：
Lei, Ting
中科院分区：
文献类型：
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作者：
Li, Ran;Zhang, Zhuo;Lei, Ting
雷公藤内酯醇是从中药雷公藤中提取的一种主要的二萜类化合物。f.根据权利要求1，几个世纪以来，其提取物已被用于治疗传统中医中的各种疾病。近年来，雷公藤内酯醇在临床前肿瘤模型中有抗肿瘤作用，但对垂体促肾上腺皮质激素腺瘤的作用尚未见报道。本研究旨在探讨雷公藤内酯醇对AtT 20小鼠促肾上腺皮质激素细胞系的抗肿瘤作用及其分子机制。我们的研究结果表明，雷公藤内酯醇抑制AtT 20细胞的细胞活力和集落数的剂量和时间依赖性模式。雷公藤内酯醇还抑制AtT 20细胞中阿黑皮素原（Pomc）mRNA的表达和细胞外促肾上腺皮质激素（ACTH）的分泌。流式细胞仪检测结果显示雷公藤内酯醇可使AtT 20细胞发生G2/M期阻滞、凋亡和线粒体膜去极化。雷公藤内酯醇处理后，caspase-3的激活呈剂量依赖性，Bcl 2/Bax比例下降。Western blot分析发现雷公藤内酯醇可抑制NF-κ B p65亚基和细胞外信号调节激酶（ERK）的磷酸化，沿着降低细胞周期蛋白D1的表达，而对NF-κ B相关蛋白如总p65、p50、I κ B α、p-I κ B α的表达无影响。此外，小鼠异种移植模型显示雷公藤甲素给药后抑制肿瘤生长和激素分泌。总之，这种化合物可能是一个潜在的药物选择，在管理库欣病。
Triptolide is a principal diterpene triepoxide from the Chinese medical plant Tripterygium wilfordii Hook. f., whose extracts have been utilized in dealing with diverse diseases in traditional Chinese medicine for centuries. Recently, the antitumor effect of triptolide has been found in several pre-clinical neoplasm models, but its effect on pituitary corticotroph adenomas has not been investigated so far. In this study, we are aiming to figure out the antitumor effect of triptolide and address the underlying molecular mechanism in AtT20 murine corticotroph cell line. Our results demonstrated that triptolide inhibited cell viability and colony number of AtT20 cells in a dose-and time-dependent pattern. Triptolide also suppressed proopiomelanocortin (Pomc) mRNA expression and extracellular adrenocorticotropic hormone (ACTH) secretion in AtT20 cells. Flow cytometry prompted that triptolide leaded to G2/M phase arrest, apoptosis program and mitochondrial membrane depolarization in AtT20 cells. Moreover, dose-dependent activation of caspase-3 and decreased Bcl2/Bax proportion were observed after triptolide treatment. By western blot analysis we found that triptolide impeded phosphorylation of NF-kappa B p65 subunit and extracellular signal-regulated kinase (ERK), along with reduction of cyclin D1, without any impact on other NF-kappa B related protein expression like total p65, p50, I kappa B alpha, p-I kappa B-alpha. Furthermore, the mouse xenograft model revealed the inhibition of tumor growth and hormone secretion after triptolide administration. Altogether this compound might be a potential pharmaceutical choice in managing Cushing's disease.