Suberoylanilide hydroxamic acid (SAHA) causes tumor growth slowdown and triggers autophagy in glioblastoma stem cells
Suberoylanilide hydroxamic acid (SAHA) causes tumor growth slowdown and triggers autophagy in glioblastoma stem cells
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DOI：
10.4161/auto.25664
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发表时间：
2013-10-01
期刊：
影响因子：
13.3
通讯作者：
Ko, Jiunn-Liang
中科院分区：
文献类型：
--
作者：
Chiao, Ming-Tsang;Cheng, Wen-Yu;Ko, Jiunn-Liang
尽管辛二酰苯胺异羟肟酸（SAHA），一种组蛋白去乙酰化酶抑制剂，已被用于癌症治疗的临床试验中，但其药理作用是通过一种知之甚少的机制发生的。在这里，我们报告说，SAHA特异性地触发自噬，并通过促进胶质母细胞瘤干细胞（GSC）晚期的凋亡来降低细胞活力。使用从胶质母细胞瘤活检培养的细胞系，我们研究了在体外SAHA处理下GSC的性质和效果。体内异种移植试验表明，SAHA有效地引起肿瘤生长减缓和诱导自噬。SAHA足以增加细胞内酸性囊泡细胞器的形成、LC 3-II向自噬体的募集、BECN 1蛋白水平的增强和SQSTM 1水平的降低。我们确定SAHA通过下调AKT-MTOR信号传导（一种主要的自噬抑制级联反应）触发自噬。有趣的是，在消耗或药理学抑制自噬后，SAHA促进细胞凋亡并导致早期细胞死亡，表明SAHA诱导的自噬功能可能充当促生存机制。此外，我们的研究结果还表明，使用氯喹抑制SAHA诱导的自噬具有协同作用，进一步增加细胞凋亡。此外，我们发现，减少剂量的SAHA作为一个有效的调制器的分化和衰老。总之，我们的研究结果为GSC的治疗提供了一个新的视角，表明SAHA是一种通过诱导自噬靶向GSC的有前途的药物。
Although suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, has been used in clinical trials for cancer therapies, its pharmacological effects occur through a poorly understood mechanism. Here, we report that SAHA specifically triggers autophagy and reduces cell viability via promotion of apoptosis in the late phase of glioblastoma stem cells (GSCs). Using a cell line cultured from a glioblastoma biopsy, we investigated the properties and effects of GSCs under SAHA treatment in vitro. In vivo xenograft assays revealed that SAHA effectively caused tumor growth slowdown and the induction of autophagy. SAHA was sufficient to increase formation of intracellular acidic vesicle organelles, recruitment of LC3-II to the autophagosomes, potentiation of BECN1 protein levels and reduced SQSTM1 levels. We determined that SAHA triggered autophagy through the downregulation of AKT-MTOR signaling, a major suppressive cascade of autophagy. Interestingly, upon depletion or pharmacological inhibition of autophagy, SAHA facilitates apoptosis and results in cell death at the early phase, suggesting that SAHA-induced autophagy functions probably act as a prosurvival mechanism. Furthermore, our results also indicated that the inhibition of SAHA-induced autophagy using chloroquine has synergistic effects that further increase apoptosis. Moreover, we found that a reduced dose of SAHA functioned as a potent modulator of differentiation and senescence. Taken together, our results provide a new perspective on the treatment of GSCs, indicating that SAHA is a promising agent for targeting GSCs through the induction of autophagy.