Valproic acid induces Notch1 signaling in small cell lung cancer cells
Valproic acid induces Notch1 signaling in small cell lung cancer cells
复制标题
DOI：
10.1016/j.jss.2008.03.008
复制
发表时间：
2008-07-01
影响因子：
2.2
通讯作者：
Chen, Herbert
中科院分区：
文献类型：
--
作者：
Platta, Christopher S.;Greenblatt, David Yue;Chen, Herbert
背景小细胞肺癌（SCLC）是一种侵袭性恶性肿瘤。目前的治疗方法的存活率很低。我们以前已经证明组蛋白去乙酰化酶（HDAC）抑制剂可以抑制神经内分泌肿瘤的生长。Notch 1信号通路的激活也损害SCLC细胞活力。在这项研究中，我们研究了HDAC抑制剂丙戊酸（VPA）激活Notch 1信号传导和抑制SCLC细胞增殖的能力。用VPA（0-10 mM）处理DMS 53人SCLC细胞2天。使用光学显微镜检查细胞形态的变化。使用针对各种Notch 1途径蛋白的抗体进行Western分析以评估Notch 1活化。此外，免疫印迹法进行了两个神经内分泌肿瘤标志物，嗜铬粒蛋白A和achaete-鳞片状复合物样1。最后，采用细胞增殖实验检测VPA对SCLC生长的影响。VPA处理后，DMS 53细胞的形态发生了显着变化。VPA诱导Notch 1蛋白的全长和活性形式的表达。此外，VPA抑制神经内分泌肿瘤标志物嗜铬粒蛋白A和ASLC-1的水平。重要的是，VPA处理导致SCLC细胞增殖的剂量依赖性抑制。HDAC抑制剂VPA激活SCLC细胞中的Notch 1信号传导。VPA诱导细胞形态学变化并抑制神经内分泌肿瘤标志物，表明表型变化。此外，VPA显著抑制SCLC细胞生长。这些结果表明，丙戊酸钠有潜力作为一种新的治疗药物的小细胞肺癌。(C)200爱思唯尔公司All rights reserved.
Background. Small cell lung cancer (SCLC) is an aggressive malignancy. Current treatments yield dismal survival rates. We have previously demonstrated that histone deacetylase (HDAC) inhibitors can inhibit neuroendocrine tumor growth. Activation of the Notch1 signaling pathway also impairs SCLC cell viability. In this study, we investigated the ability of the HDAC inhibitor valproic acid (VPA) to activate Notch1 signaling and inhibit proliferation in SCLC cells.Materials and methods. DMS53 human SCLC cells were treated with VPA (0-10 mM) for 2 d. Light microscopy was used to examine changes in cell morphology. Western analysis was performed using antibodies against various Notch1 pathway proteins to assess Notch1 activation. Additionally, immunoblotting was performed for two neuroendocrine tumor markers, chromogranin A and achaete-scute complex-like 1. Finally, a cell proliferation assay was used to measure the effects of VPA on SCLC growth over 8 d.Results. After treatment with VPA, DMS53 cells underwent dramatic changes in morphology. VPA induced expression of the full-length and active forms of Notch1 protein. Furthermore, VPA suppressed levels of neuroendocrine tumor markers chromogranin A and ASLC-1. Importantly, VPA treatment led to dose-dependent inhibition of SCLC cell proliferation.Conclusions. The HDAC inhibitor VPA activates Notch1 signaling in SCLC cells. VPA induces changes in cell morphology and suppresses neuroendocrine tumor markers, indicating a change in phenotype. Additionally, VPA profoundly inhibits SCLC cell growth. These results suggest that VPA has potential as a novel therapeutic agent for SCLC. (C) 200 Elsevier Inc. All rights reserved.