Kang Dong Wan, Choi Chang Hwa, Park Ji Yeon, Kang Soo Kyung, Kim Yong Keun
Department of Neurosurgery, College of Medicine, Pusan National University, Pusan 602-739, Korea.
Neurochem Res. 2008 Mar;33(3):551-61. doi: 10.1007/s11064-007-9475-x. Epub 2007 Oct 17.
Induction of apoptosis may be a promising therapeutic approach in cancer therapy. Peroxisome proliferator-activated receptor-gamma (PPAR gamma) agonists induce apoptosis in various cancer cells. However, the molecular mechanism remains to be defined. The present study was undertaken to determine the precise mechanism of cell death induced by ciglitazone, a synthetic PPAR gamma agonist, in A172 human glioma cells. Ciglitazone resulted in a concentration- and time-dependent apoptotic cell death. Similar results were obtained with troglitazone, another synthetic PPAR gamma agonist. Ciglitazone induced reactive oxygen species (ROS) generation and ciglitazone-induced cell death was prevented by the antioxidant N-acetylcysteine, suggesting an important role of ROS generation in the ciglitazone-induced cell death. The cell death induced by ciglitazone was inhibited by the PPAR gamma antagonist GW9662. Although ciglitazone treatment caused a transient activation of extracellular signal-regulated kinase (ERK) and p38, the ciglitazone-induced cell death was not affected by inhibitors of these kinses. Ciglitazone caused a loss of mitochondrial membrane potential and its effect was prevented by N-acetylcysteine and GW9662. The specific inhibitor of caspases-3 DEVD-CHO and the general caspase inhibitor z-DEVD-FMK did not exert the protective effect against the ciglitazone-induced cell death and caspase-3 activity also was not altered by ciglitazone. The ciglitazone-induced cell death was accompanied by down-regulation of XIAP and Survivin, but not by release of apoptosis-inducing factor. Taken together, these findings suggest that down-regulation of XIAP and Survivin may play an active role in mediating a caspase-independent and -PPAR gamma-dependent cell death induced by ciglitazone in A172 human glioma cells. These data may provide a novel insight into potential therapeutic strategies for treatment of glioblastoma.
诱导细胞凋亡可能是癌症治疗中一种有前景的治疗方法。过氧化物酶体增殖物激活受体γ（PPARγ）激动剂可诱导多种癌细胞凋亡。然而，其分子机制仍有待确定。本研究旨在确定合成的PPARγ激动剂环格列酮诱导A172人胶质瘤细胞死亡的精确机制。环格列酮导致细胞凋亡呈浓度和时间依赖性。另一种合成的PPARγ激动剂曲格列酮也得到了类似结果。环格列酮诱导活性氧（ROS）生成，抗氧化剂N-乙酰半胱氨酸可阻止环格列酮诱导的细胞死亡，这表明ROS生成在环格列酮诱导的细胞死亡中起重要作用。PPARγ拮抗剂GW9662可抑制环格列酮诱导的细胞死亡。尽管环格列酮处理可引起细胞外信号调节激酶（ERK）和p38的短暂激活，但环格列酮诱导的细胞死亡不受这些激酶抑制剂的影响。环格列酮导致线粒体膜电位丧失，N-乙酰半胱氨酸和GW9662可阻止其作用。半胱天冬酶-3特异性抑制剂DEVD-CHO和通用半胱天冬酶抑制剂z-DEVD-FMK对环格列酮诱导的细胞死亡没有保护作用，环格列酮也未改变半胱天冬酶-3的活性。环格列酮诱导的细胞死亡伴随着X连锁凋亡抑制蛋白（XIAP）和生存素的下调，但不伴有凋亡诱导因子的释放。综上所述，这些发现表明XIAP和生存素的下调可能在介导环格列酮在A172人胶质瘤细胞中诱导的非半胱天冬酶依赖性和PPARγ依赖性细胞死亡中起积极作用。这些数据可能为胶质母细胞瘤的潜在治疗策略提供新的见解。
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