Arsenic trioxide induces autophagy and apoptosis in human glioma cells in vitro and in vivo through downregulation of survivin
Arsenic trioxide induces autophagy and apoptosis in human glioma cells in vitro and in vivo through downregulation of survivin
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DOI：
10.1007/s00109-011-0763-1
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发表时间：
2011-09-01
影响因子：
4.7
通讯作者：
Wang, Ying-Jan
中科院分区：
文献类型：
--
作者：
Chiu, Hui-Wen;Ho, Yuan-Soon;Wang, Ying-Jan
胶质瘤是所有人类恶性肿瘤中最具侵袭性的。Survivin在胶质瘤中过度表达，Survivin的过度表达与胶质瘤的进展和胶质瘤患者的不良预后有关。三氧化二砷（ATO）用于急性早幼粒细胞白血病患者，并在体外对几种实体肿瘤细胞系有活性。本研究以人胶质瘤细胞系U118-MG为实验对象，研究ATO在体外和体内的抗癌作用。分析了细胞死亡（自噬和凋亡）与存活素关系的分子机制。ATO以浓度依赖的方式通过增加有丝分裂细胞来降低细胞活力。ato诱导自噬和凋亡的机制是通过抑制PI3K/Akt和激活MAPK信号通路介导的。用PI3K/AKT和MAPK特异性化学抑制剂预处理U118-MG细胞后，ATO显著改变了细胞毒性和survivin的表达，表明survivin在ATO诱导的细胞死亡中起关键作用。用survivin shRNA转染U118-MG细胞后，凋亡细胞和自噬细胞显著增加。在体内研究中，ATO处理SCID小鼠显示出明显的肿瘤生长延迟时间和肿瘤组织中survivin的表达降低。本研究的一个重要结果是发现survivin可以抑制胶质瘤细胞的自噬和凋亡。本研究提示ATO治疗或survivin抑制可能是恶性胶质瘤的一种新的治疗策略。
Gliomas are the most aggressive of all human malignancies. Survivin is overexpressed in gliomas, and overexpression of survivin is associated with the progression of gliomas and the poor prognosis of glioma patients. Arsenic trioxide (ATO) is used in patients with acute promyelocytic leukemia and is active in vitro in several solid tumor cell lines. In the present study, the human glioma cell line U118-MG was used to investigate the anti-cancer effect of ATO in vitro and in vivo. The molecular mechanisms of the relationship between cell death (autophagy and apoptosis) and survivin were analyzed. ATO reduced cell viability through an increase in mitotic cells in a concentration-dependent manner. The mechanisms of ATO-induced autophagy and apoptosis were mediated by the inhibition of PI3K/Akt and the activation of MAPK signaling pathways. The ATO treatment of U118-MG cells pre-treated with specific chemical inhibitors of PI3K/AKT and MAPK significantly changed the cytotoxicity and the expression of survivin, suggesting that survivin plays a pivotal role in ATO-induced cell death. When U118-MG cells were transfected with survivin shRNA, the results demonstrated a significant increase in apoptotic and autophagic cells. In in vivo studies, the ATO treatment of SCID mice showed a significant tumor growth delay time and the decreased expression of survivin in tumor tissue. An important result from the current study is the finding that survivin could suppress both autophagy and apoptosis in glioma cells. This study suggests that ATO treatment or survivin inhibition could be a novel therapeutic strategy in malignant gliomas.