Abstract
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.
Highlights
Glioblastoma (GBM) is an extremely deadly form of brain cancer with limited treatment options and novel therapeutic modalities are necessary
SRT2183 suppresses glioma cell growth We first investigated whether SRT2183 was an effective inhibitor of glioma cell viability
Pharmacological inhibition of either NF-κB or STAT3 enhances SRT2183-mediated glioma cell death Given the inhibitory effects by SRT2183 on glioma cell growth, we examined whether SRT2183 affects the acetylation of STAT3 and NF-κB, two well-known substrates of Sirt1 in glioma cells [1, 2]
Summary
Glioblastoma (GBM) is an extremely deadly form of brain cancer with limited treatment options and 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 Sirt activator SRT2183 in glioma cell lines in terms of biological response. The current treatment standard for newly diagnosed GBM comprises surgery, radiation, and chemotherapy, with temozolomide (TMZ). GBM cells display inherent resistance to TMZ as well as other cytotoxic drugs. Epigenetic mechanisms, i.e. addition and removal of acetyl groups to the protein possess a critical function with cancer pathogenesis, including GBM. [6], indicating that Sirt functions as an oncogene in GBM A recent study demonstrates that neural stem cells need Sirt to transform into “neural cancer stem cells” and aids for the survival of these transmuted cells in a p53 dependent fashion. [6], indicating that Sirt functions as an oncogene in GBM
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