Sirtuin1 activator SRT2183 suppresses glioma cell growth involving activation of endoplasmic reticulum stress pathway
Abstract Background Glioblastoma (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 informa...
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doaj-8cfd61fd4bc54c668afb71b8eb73dff12020-11-25T03:02:28ZengBMCBMC Cancer1471-24072019-07-0119111110.1186/s12885-019-5852-5Sirtuin1 activator SRT2183 suppresses glioma cell growth involving activation of endoplasmic reticulum stress pathwayTian Ye0Liwen Wei1Ji Shi2Ke Jiang3Huizhe Xu4Lulu Hu5Lingkai Kong6Ye Zhang7Songshu Meng8Haozhe Piao9Department of Neurosurgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & InstituteDepartment of Neurosurgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & InstituteDepartment of Neurosurgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & InstituteInstitute of Cancer Stem Cell, Dalian Medical University Cancer CenterInstitute of Cancer Stem Cell, Dalian Medical University Cancer CenterInstitute of Cancer Stem Cell, Dalian Medical University Cancer CenterInstitute of Cancer Stem Cell, Dalian Medical University Cancer CenterDepartment of Neurosurgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & InstituteInstitute of Cancer Stem Cell, Dalian Medical University Cancer CenterDepartment of Neurosurgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & InstituteAbstract Background Glioblastoma (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. Methods The 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. Results SRT2183 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. Conclusions Our 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.http://link.springer.com/article/10.1186/s12885-019-5852-5Sirt1Endoplasmic reticulum stressGliomaSTAT3NF-κB |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Tian Ye Liwen Wei Ji Shi Ke Jiang Huizhe Xu Lulu Hu Lingkai Kong Ye Zhang Songshu Meng Haozhe Piao |
spellingShingle |
Tian Ye Liwen Wei Ji Shi Ke Jiang Huizhe Xu Lulu Hu Lingkai Kong Ye Zhang Songshu Meng Haozhe Piao Sirtuin1 activator SRT2183 suppresses glioma cell growth involving activation of endoplasmic reticulum stress pathway BMC Cancer Sirt1 Endoplasmic reticulum stress Glioma STAT3 NF-κB |
author_facet |
Tian Ye Liwen Wei Ji Shi Ke Jiang Huizhe Xu Lulu Hu Lingkai Kong Ye Zhang Songshu Meng Haozhe Piao |
author_sort |
Tian Ye |
title |
Sirtuin1 activator SRT2183 suppresses glioma cell growth involving activation of endoplasmic reticulum stress pathway |
title_short |
Sirtuin1 activator SRT2183 suppresses glioma cell growth involving activation of endoplasmic reticulum stress pathway |
title_full |
Sirtuin1 activator SRT2183 suppresses glioma cell growth involving activation of endoplasmic reticulum stress pathway |
title_fullStr |
Sirtuin1 activator SRT2183 suppresses glioma cell growth involving activation of endoplasmic reticulum stress pathway |
title_full_unstemmed |
Sirtuin1 activator SRT2183 suppresses glioma cell growth involving activation of endoplasmic reticulum stress pathway |
title_sort |
sirtuin1 activator srt2183 suppresses glioma cell growth involving activation of endoplasmic reticulum stress pathway |
publisher |
BMC |
series |
BMC Cancer |
issn |
1471-2407 |
publishDate |
2019-07-01 |
description |
Abstract Background Glioblastoma (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. Methods The 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. Results SRT2183 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. Conclusions Our 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. |
topic |
Sirt1 Endoplasmic reticulum stress Glioma STAT3 NF-κB |
url |
http://link.springer.com/article/10.1186/s12885-019-5852-5 |
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