GSK3β/β-catenin signaling is correlated with the differentiation of glioma cells induced by wogonin
GSK3β/β-catenin signaling is correlated with the differentiation of glioma cells induced by wogonin
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DOI：
10.1016/j.toxlet.2013.07.013
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发表时间：
2013-10-24
影响因子：
3.5
通讯作者：
Guo, Qinglong
中科院分区：
文献类型：
--
作者：
Wang, Yajing;Zhang, Yi;Guo, Qinglong
恶性神经胶质瘤是最常见和最具侵袭性的原发性脑肿瘤，分化治疗已成为一种有前途的候选策略。在这项研究中，我们使用体外和体内测定来检查汉黄芩素（黄芩的主要活性成分）对神经胶质瘤 C6 和 U251 细胞的分化作用。我们发现汉黄芩素能够以浓度依赖性方式抑制细胞增殖并诱导G0/G1期阻滞。汉黄芩素还引发 G1 细胞周期调节蛋白细胞周期蛋白 D1、细胞周期蛋白依赖性激酶 2 和 4 的显着减少，以及细胞周期抑制蛋白 p27 的过度表达。免疫荧光和蛋白质印迹分析表明汉黄芩素增加谱系特异性分化标志物胶质纤维酸性蛋白（GFAP）的表达。在机制方面，我们验证了汉黄芩素显着降低了蛋白激酶 B (AKT) 的磷酸化水平，并且β-连环蛋白低表达水平的维持依赖于糖原合酶激酶 3 beta (GSK3 beta) 在 Ser9 的激活。使用经典激活剂氯化锂 (LiCl) 和抑制剂 dickkopf-1 (Dkk1) 阻断 GSK3 β/β-连环蛋白途径是汉黄芩素诱导的增殖抑制和终末分化所必需的。此外，静脉注射汉黄芩素可延缓颅内肿瘤模型中C6神经胶质瘤的生长。这些发现为基于汉黄芩素的恶性胶质母细胞瘤分化疗法提供了证据和机制支持。此外，GSK3 β/β-catenin 通路的抑制可能是神经胶质瘤分化的关键和必要因素。 (C) 2013 作者。由爱思唯尔爱尔兰有限公司出版。保留所有权利。
Malignant gliomas are the most common and most aggressive primary brain tumor, and for which differentiation therapy has emerged as a promising candidate strategy. In this study, we used in vitro and in vivo assays to examine the differentiation effects of wogonin, a major active constituent of Scutellaria baicalensis, on glioma C6 and U251 cells. We found that wogonin can suppress cell proliferation and induce G0/G1 arrest under a concentration-dependent manner. Wogonin also triggered significant reduction in the G1 cell-cycle regulatory proteins cyclin D1, cyclin-dependent kinase 2 and 4 along with overexpression of cell-cycle inhibitory proteins p27. Immunofluorescence and western blot analysis indicated that wogonin increased the expression of lineage-specific differentiation marker glial fibrillary acidic protein (GFAP). In mechanisms, we verified that wogonin significantly diminished the phosphorylated level of protein kinase B (AKT), and maintenance of low beta-catenin expression level was dependent on glycogen synthase kinase 3 beta (GSK3 beta) activation at Ser9. Blocking GSK3 beta/beta-catenin pathway was required for wogonin-induced proliferation inhibition and terminal differentiation by using canonical activator lithium chloride (LiCl) and inhibitor dickkopf-1 (Dkk1). Moreover, intravenous administration of wogonin delayed the growth of C6 glioma in the intracranial tumor model. These findings provide the evidence and mechanistic support for wogonin-based differentiation therapies for malignant glioblastoma. Furthermore, inhibition of GSK3 beta/beta-catenin pathway may be a key and requisite factor in glioma differentiation. (C) 2013 The Authors. Published by Elsevier Ireland Ltd. All rights reserved.