Suberoylanilide hydroxamic acid represses glioma stem-like cells.
Suberoylanilide hydroxamic acid represses glioma stem-like cells.
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DOI：
10.1186/s12929-016-0296-6
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发表时间：
2016-11-18
影响因子：
11
通讯作者：
Chuang JY
中科院分区：
文献类型：
--
作者：
Hsu CC;Chang WC;Hsu TI;Liu JJ;Yeh SH;Wang JY;Liou JP;Ko CY;Chang KY;Chuang JY
胶质瘤干细胞（GSCs）被认为在多形性胶质母细胞瘤（GBM）治疗中具有高耐药性。为了找到旨在降低GSC干性和提高GBM患者生存率的新策略，我们研究了组蛋白去乙酰化酶（HDAC）抑制剂亚eroylanilide羟肟酸（SAHA）的作用和机制，因为HDAC活性与癌症干细胞样细胞（CSC）的丰度和性质有关。将人GBM细胞系镀于无血清悬浮培养中，使其能够形成球体并富集CSC。随后，在SAHA处理后，检测GSCs的干性标志物、细胞增殖、活力以及细胞凋亡和衰老，以明确是否发生抑制GSCs。我们证明了SAHA可以减弱GSCs中的细胞增殖并降低干细胞相关标志物（CD133和Bmi1）的表达。此外，在高浓度（大于5 μM）下，SAHA触发GSCs凋亡，同时增加caspase 8-和caspase 9介导通路的激活。有趣的是，我们发现低剂量的SAHA （1 μM和2.5 μM）通过细胞周期阻滞抑制GSCs，并通过p53上调和p38激活诱导GSCs过早衰老。在GSCs中，SAHA通过p38-p53通路诱导细胞凋亡并作为一种有效的衰老调节剂发挥作用。我们的研究结果为通过SAHA治疗GSCs提供了一个新的视角，并表明SAHA可以作为一种有效的药物来克服GBM患者的耐药性。本文的在线版本（doi:10.1186/s12929-016-0296-6）包含补充材料，可供授权用户使用。
Glioma stem-like cells (GSCs) are proposed to be responsible for high resistance in glioblastoma multiforme (GBM) treatment. In order to find new strategies aimed at reducing GSC stemness and improving GBM patient survival, we investigated the effects and mechanism of a histone deacetylases (HDACs) inhibitor, suberoylanilide hydroxamic acid (SAHA), since HDAC activity has been linked to cancer stem-like cell (CSC) abundance and properties. Human GBM cell lines were plated in serum-free suspension cultures allowed for sphere forming and CSC enrichment. Subsequently, upon SAHA treatment, the stemness markers, cell proliferation, and viability of GSCs as well as cellular apoptosis and senescence were examined in order to clarify whether inhibition of GSCs occurs. We demonstrated that SAHA attenuated cell proliferation and diminished the expression stemness-related markers (CD133 and Bmi1) in GSCs. Furthermore, at high concentrations (more than 5 μM), SAHA triggered apoptosis of GSCs accompanied by increases in both activation of caspase 8- and caspase 9-mediated pathways. Interestingly, we found that a lower dose of SAHA (1 μM and 2.5 μM) inhibited GSCs via cell cycle arrest and induced premature senescence through p53 up-regulation and p38 activation. SAHA induces apoptosis and functions as a potent modulator of senescence via the p38-p53 pathway in GSCs. Our results provide a perspective on targeting GSCs via SAHA treatment, and suggest that SAHA could be used as a potent agent to overcome drug resistance in GBM patients. The online version of this article (doi:10.1186/s12929-016-0296-6) contains supplementary material, which is available to authorized users.
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5.3
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