title: Sirtuin-2 activity is required for glioma stem cell proliferation arrest but not necrosis induced by resveratrol.
abstract: Glioblastomas, the most common form of primary brain tumors, are the fourth cause of death by cancer in adults. Increasing evidences suggest that glioblastoma resistance to existing radio- and chemotherapies rely on glioblastoma stem cells (GSCs). GSCs are endowed with a unique combination of stem-like properties alike to normal neural stem cells (NSCs), and of tumor initiating properties. The natural polyphenol resveratrol is known to exert opposite actions on neural cells according to their normal or cancerous status. Here, we used resveratrol to explore the molecular mechanisms differing between GSCs and NSCs. We observed a dual action of resveratrol on GSCs: resveratrol blocked GSC proliferation up to 150 μM and induced their necrosis at higher doses. On the opposite, resveratrol had no effect on NSC behavior. To determine the mechanisms underlying resveratrol effects, we focused our attention on the family of NAD-dependent deacetylases sirtuins (SIRT). A member of this family, SIRT1, has been repetitively shown to constitute a preferential resveratrol target, at least in normal cells. Western blot analysis showed that SIRT1 and SIRT3 were expressed by both GSCs and NSCs whereas SIRT2 expression was restricted to GSCs. Pharmacological blockade of SIRT2 activity or down-regulation of SIRT2 expression with siRNAs counteracted the inhibitory effect of resveratrol on cell proliferation. On the contrary, inhibition of SIRT2 activity or expression did not counteract GSC necrosis observed in presence of high doses of resveratrol. Our results highlight SIRT2 as a novel target for altering GSC properties.
authors: Team Glial Plasticity, U894 Inserm, Université Paris Descartes, Paris, France.
authors: Salwa
authors: S
authors: Sayd
authors: Cécile
authors: C
authors: Thirant
authors: Elias A
authors: EA
authors: El-Habr
authors: Joanna
authors: J
authors: Lipecka
authors: Luiz Gustavo
authors: LG
authors: Dubois
authors: Alexandra
authors: A
authors: Bogeas
authors: Nadia
authors: N
authors: Tahiri-Jouti
authors: Hervé
authors: H
authors: Chneiweiss
authors: Marie-Pierre
authors: MP
authors: Junier
mesh_terms: D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D009336:Necrosis / Q000139:chemically induced*; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D000077185:Resveratrol; D056565:Sirtuin 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013267:Stilbenes / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D034741:RNA, Small Interfering; D013267:Stilbenes; C474199:SIRT2 protein, human; D056565:Sirtuin 2; D000077185:Resveratrol
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