Department of Environmental and Occupational Health, National Cheng Kung University Medical College, 138 Sheng-Li Road, Tainan 704, Taiwan.
J Mol Med (Berl). 2011 Sep;89(9):927-41. doi: 10.1007/s00109-011-0763-1. Epub 2011 May 19.
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.
神经胶质瘤是所有人类恶性肿瘤中侵袭性最强的。Survivin 在神经胶质瘤中过度表达，Survivin 的过度表达与神经胶质瘤的进展和神经胶质瘤患者的不良预后相关。三氧化二砷（ATO）用于治疗急性早幼粒细胞白血病，并且在几种实体肿瘤细胞系中具有体外活性。在本研究中，使用人神经胶质瘤细胞系 U118-MG 来研究 ATO 在体外和体内的抗癌作用。分析了细胞死亡（自噬和细胞凋亡）与 survivin 之间关系的分子机制。ATO 通过增加有丝分裂细胞以浓度依赖性方式降低细胞活力。ATO 诱导自噬和细胞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 的特定化学抑制剂预处理的 U118-MG 细胞用 ATO 处理，明显改变了细胞毒性和 survivin 的表达，这表明 survivin 在 ATO 诱导的细胞死亡中起关键作用。当 U118-MG 细胞用 survivin shRNA 转染时，结果表明凋亡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 表达降低。本研究的一个重要结果是发现 survivin 可以抑制神经胶质瘤细胞中的自噬和细胞凋亡。本研究表明，ATO 治疗或 survivin 抑制可能是恶性神经胶质瘤的一种新的治疗策略。
