Team Glial Plasticity, U894 Inserm, Université Paris Descartes, Paris, France.
Stem Cell Rev Rep. 2014 Feb;10(1):103-13. doi: 10.1007/s12015-013-9465-0.
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.
胶质母细胞瘤是最常见的原发性脑肿瘤，是成年人癌症死亡的第四大原因。越来越多的证据表明，胶质母细胞瘤对现有放射和化疗的耐药性依赖于胶质母细胞瘤干细胞（GSCs）。GSCs具有与正常神经干细胞（NSCs）相似的独特的干细胞特性组合，以及肿瘤起始特性。天然多酚白藜芦醇已知根据其正常或癌变状态对神经细胞发挥相反的作用。在这里，我们使用白藜芦醇来探索 GSCs 和 NSCs 之间不同的分子机制。我们观察到白藜芦醇对 GSCs 的双重作用：白藜芦醇在 150μM 时阻止 GSC 增殖，并在更高剂量时诱导其坏死。相反，白藜芦醇对 NSC 行为没有影响。为了确定白藜芦醇作用的机制，我们将注意力集中在 NAD 依赖性去乙酰化酶 SIRT 家族上。该家族的一个成员 SIRT1 已被反复证明是至少在正常细胞中白藜芦醇的优先靶标。Western blot 分析表明，SIRT1 和 SIRT3 均由 GSCs 和 NSCs 表达，而 SIRT2 表达仅限于 GSCs。用 SIRT2 抑制剂或 siRNA 下调 SIRT2 表达抑制 SIRT2 活性，可拮抗白藜芦醇对细胞增殖的抑制作用。相反，在高剂量白藜芦醇存在下，抑制 SIRT2 活性或表达并不能拮抗观察到的 GSC 坏死。我们的结果强调了 SIRT2 作为改变 GSC 特性的新靶标。
