Histone deacetylase inhibitors upregulate Notch-1 and inhibit growth in pheochromocytoma cells.
Histone deacetylase inhibitors upregulate Notch-1 and inhibit growth in pheochromocytoma cells.
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DOI：
10.1016/j.surg.2008.08.027
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发表时间：
2008-12
期刊：
影响因子：
3.8
通讯作者：
Chen, Herbert
中科院分区：
文献类型：
--
作者：
Adler, Joel T.;Hottinger, Daniel G.;Kunnimalaiyaan, Muthusamy;Chen, Herbert
组蛋白去乙酰化酶（HDAC）抑制剂丙戊酸（VPA）和亚甲基双羟肟酸（SBHA）最近被证明是强Notch1激活剂。Notch1通路的上调已被证明可以限制神经内分泌（NE）肿瘤的生长和抑制激素分泌。我们假设抑制HDAC可能是激活Notch1通路并抑制嗜铬细胞瘤细胞生长和激素分泌的有效策略。嗜铬细胞瘤PC-12细胞用8 mM VPA或40µM SBHA处理2天。治疗后检测NE肿瘤标志物棘鳞复合体样1 （ASCL1）和嗜铬粒蛋白A （CgA）。通过细胞增殖试验评估生长情况，Western分析确定生长调节机制。HDAC抑制剂治疗引起ASCL1和CgA的剂量依赖性降低，同时增加活性Notch1蛋白的量。治疗6天后，观察到剂量依赖性生长抑制和凋亡标志物caspase-3和PARP的裂解。VPA和SBHA能有效上调Notch1，抑制NE肿瘤标志物，并通过体外嗜铬细胞瘤细胞凋亡抑制细胞生长。用HDAC抑制剂激活Notch1信号通路可能是治疗嗜铬细胞瘤的一种新策略。
The histone deacetylase (HDAC) inhibitors valproic acid (VPA) and suberoyl bis-hydroxamic acid (SBHA) have recently been demonstrated to be strong Notch1 activators. Upregulation of the Notch1 pathway has been shown to limit growth and suppress hormonal secretion in neuroendocrine (NE) tumors. We hypothesized that HDAC inhibition would be an effective strategy to activate the Notch1 pathway and inhibit growth and hormonal secretion in pheochromocytoma cells. Pheochromocytoma PC-12 cells were treated with up to 8 mM VPA or 40 µM SBHA for 2 days. NE tumor markers achaete-scute complex-like 1 (ASCL1) and chromogranin A (CgA) were measured after treatment by Western analysis. Growth was assessed by a cellular proliferation assay, and Western analysis was used to determine the mechanism of growth regulation. HDAC inhibitor treatment caused a dose-dependent decrease in ASCL1 and CgA while increasing the amount of active Notch1 protein. With 6 day treatment, dose-dependent growth inhibition and cleavage of the apoptotic markers caspase-3 and PARP was observed. VPA and SBHA effectively upregulate Notch1, suppress NE tumor markers, and decrease growth via apoptosis of pheochromocytoma cells in vitro. Activation of the Notch1 signaling pathway with HDAC inhibitors may represent a new strategy to treat pheochromocytomas.
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影响因子：
9
作者：
Greenblatt, David Yu;Cayo, Max A.;Chen, Herbert
通讯作者：
Chen, Herbert
影响因子：
5.8
作者：
Kunnimalaiyaan, Muthusamy;Chen, Herbert
通讯作者：
Chen, Herbert
影响因子：
2.2
作者：
Platta, Christopher S.;Greenblatt, David Yue;Chen, Herbert
通讯作者：
Chen, Herbert
DOI：
10.1097/00000421-199908000-00008
发表时间：
1999-08-01
影响因子：
2.6
作者：
Sisson, JC;Shapiro, B;Spaulding, S
通讯作者：
Spaulding, S
影响因子：
5.8
作者：
Mantero, F;Terzolo, M;Angeli, A
通讯作者：
Angeli, A