Sirtuin1 activator SRT2183 suppresses glioma cell growth involving activation of endoplasmic reticulum stress pathway
Sirtuin1 activator SRT2183 suppresses glioma cell growth involving activation of endoplasmic reticulum stress pathway
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Sirtuin1 激活剂 SRT2183 抑制神经胶质瘤细胞生长，涉及激活内质网应激通路
DOI：
10.1186/s12885-019-5852-5
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发表时间：
2019-07-18
期刊：
影响因子：
3.8
通讯作者：
Piao, Haozhe
中科院分区：
文献类型：
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作者：
Ye, Tian;Wei, Liwen;Piao, Haozhe
背景胶质母细胞瘤（GBM）是一种非常致命的脑癌，治疗选择有限，因此需要新的治疗方法。组蛋白去乙酰化酶抑制剂（HDACi）已经证明了对GBM的临床和临床前活性。（沉默交配型信息调节2同源物，Sirt1）缩写为Sirtuin 1，与GBM有关。我们探讨了Sirt1激活剂SRT 2183在胶质瘤细胞系中的生物学responsibility.MethodsThe胶质瘤细胞生长和神经球生存的影响SRT 2183的活性进行了评估，在体外使用CCK-8，克隆形成和神经球测定，分别。流式细胞术检测胶质瘤细胞周期阻滞和凋亡。通过检测GFP-微管相关蛋白1轻链3（GFP-LC 3）斑点、LC 3的非脂化形式（LC 3-I）转化为磷脂酰乙醇胺结合形式（LC 3-II），研究了SRT 2183诱导的自噬。用免疫沉淀法检测SRT 2183处理的胶质瘤细胞中STAT3和NF-κ B的乙酰化。结果SRT 2183能抑制胶质瘤细胞的生长，并能破坏胶质瘤细胞内的神经球。此外，SRT 2183诱导胶质瘤细胞周期阻滞和凋亡，伴随着促凋亡Bim的上调和Bcl-2和Bcl-xL的下调。值得注意的是，当暴露于SRT 2183时，在神经胶质瘤细胞中触发ER应激，而预暴露于ER应激抑制剂4-PBA，显著拮抗SRT 2183介导的神经胶质瘤细胞生长抑制。此外，SRT 2183诱导神经胶质瘤细胞中的自噬，自噬的药理学调节似乎不影响SRT 2183抑制的细胞生长。SRT 2183对胶质瘤细胞p65 NF-κ B和STAT 3乙酰化和磷酸化的影响不同。结论ER应激通路参与了SRT 2183对胶质瘤细胞生长的抑制作用。需要进一步的体内研究来巩固数据。
BackgroundGlioblastoma (GBM) is an extremely deadly form of brain cancer with limited treatment options and thus novel therapeutic modalities are necessary. Histone deacetylase inhibitors (HDACi) have demonstrated clinical and preclinical activities against GBM. (Silent mating type information regulation 2 homolog, Sirt1) abbreviated as Sirtuin 1, has been implicated in GBM. We explored the activity of the Sirt1 activator SRT2183 in glioma cell lines in terms of biological response.MethodsThe effects of SRT2183 on glioma cell growth and neurosphere survival were evaluated in vitro using the CCK-8, clonogenic and neurosphere assays, respectively. Glioma cell cycle arrest and apoptosis were determined by flow cytometry. SRT2183-induced autophagy was investigated by detection of GFP-microtubule-associated protein 1 light chain 3 (GFP-LC3) puncta, conversion of the nonlipidated form of LC3 (LC3-I) to the phosphatidylethanolamine-conjugated form (LC3-II). Acetylation of STAT3 and NF-κB in SRT2183-treated glioma cells was examined using immunoprecipitation. The expression levels of anti-apoptotic proteins were assayed by immunoblotting.ResultsSRT2183 suppressed glioma cell growth and destroyed neurospheres in vitro. Furthermore, SRT2183 induced glioma cell cycle arrest and apoptosis, accompanying by upregulation of the pro-apoptotic Bim and downregulation of Bcl-2 and Bcl-xL. Notably, ER stress was triggered in glioma cells upon exposure to SRT2183 while the pre-exposure to 4-PBA, an ER stress inhibitor, significantly antagonized SRT2183-mediated growth inhibition in glioma cells. In addition, SRT2183 induced autophagy in glioma cells and pharmacological modulation of autophagy appeared not to affect SRT2183-inhibited cell growth. Of interest, the acetylation and phosphorylation of p65 NF-κB and STAT3 in glioma cells were differentially affected by SRT2183.ConclusionsOur data suggest the ER stress pathway is involved in SRT2183-mediated growth inhibition in glioma. Further investigation in vivo is needed to consolidate the data.