Valproic acid activates Notch1 signaling and induces apoptosis in medullary thyroid cancer cells
Valproic acid activates Notch1 signaling and induces apoptosis in medullary thyroid cancer cells
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DOI：
10.1097/sla.0b013e3181758d0e
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发表时间：
2008-06-01
影响因子：
9
通讯作者：
Chen, Herbert
中科院分区：
文献类型：
--
作者：
Greenblatt, David Yu;Cayo, Max A.;Chen, Herbert
目的：研究丙戊酸（VPA）对甲状腺髓样癌（MTC）细胞中Notch 1表达和癌细胞增殖的影响。背景：除了手术外，没有有效的治疗MTC的方法，MTC是一种经常转移的神经内分泌恶性肿瘤。我们先前已经表明，在MTC细胞中Notch 1的过表达抑制细胞生长和激素产生。VPA是一种长期用于治疗癫痫的药物，最近被确定为潜在的Notch 1激活剂。方法：用VPA（0-5 mM）处理人MTC细胞，Western blotting检测Notch 1通路蛋白和神经内分泌肿瘤标志物的水平。在确认VPA是MTC细胞中的Notch 1激活剂后，我们进行了细胞增殖测定。最后，为了确定生长抑制的机制，我们测量了各种凋亡标志物的蛋白水平。VPA处理导致全长和活性Notch 1蛋白的增加。VPA激活Notch 1可抑制2种神经内分泌肿瘤标志物ASCL 1和嗜铬粒蛋白A。重要的是，VPA以剂量依赖性方式抑制MTC细胞的生长。免疫印迹分析表明caspase激活和聚（ADP-核糖）聚合酶裂解，表明诱导apoptosis.Conclusions：VPA激活MTC细胞中Notch 1信号转导，并通过诱导凋亡抑制其生长。由于VPA在人体中的安全性已得到充分证实，因此可以在不久的将来启动使用该药物治疗晚期MTC患者的临床试验。
Objective: To examine the effects of valproic acid (VPA) on Notch1 expression and cancer cell proliferation in medullary thyroid cancer (MTC) cells.Background: Other than surgery, there are no effective treatments for MTC, a neuroendocrine malignancy that frequently metastasizes. We have previously shown that over-expression of Notch1 in MTC cells inhibits cell growth and hormone production. VPA, a drug long used for the treatment of epilepsy, has recently been identified as a potential Notch1 activator. We hypothesized that VPA might activate Notch1 signaling in MTC cells, with antiproliferative effects.Methods: Human MTC cells were treated with VPA (0-5 mM) and Western blotting was performed to measure levels of Notch1 paths way proteins and neuroendocrine tumor markers. After confirming that VPA is a Notch1 activator in MTC cells, we performed cell proliferation assay. Finally, to determine the mechanism of growth inhibition, we measured protein levels of various markers of apoptosis.Results: Notch1 was absent in MTC cells at baseline. VPA treatment resulted in an increase in both full-length and active Notch1 protein. Notch1 activation with VPA suppressed 2 neuroendocrine tumor markers, ASCL1 and chromogranin A. Importantly, VPA inhibited the growth of MTC cells in a dose-dependent manner. Immunoblot analysis demonstrated caspase activation and poly(ADP-ribose) polymerase cleavage, indicating the induction of apoptosis.Conclusions: VPA activates Notch1 signaling in MTC cells and inhibits their growth by inducing apoptosis. As the safety of VPA in human beings is well established, a clinical trial using this drug to treat patients with advanced MTC could be initiated in the near future.