Zhou Jinhong, Ye Jian, Zhao Xiaojia, Li Aiping, Zhou Jianwei
Department of Molecular Cell Biology and Toxicology, Institute of Toxicology, School of Public Health, Nanjing Medical University, 140 Hanzhong Road, Nanjing 210029, People's Republic of China.
Toxicol Appl Pharmacol. 2008 Jul 1;230(1):33-40. doi: 10.1016/j.taap.2008.01.041. Epub 2008 Feb 20.
Arsenic trioxide, emerging as a standard therapy for refractory acute promyelocytic leukemia, induces apoptosis in a variety of malignant cell lines. JWA, a novel retinoic acid-inducible gene, is known to be involved in apoptosis induced by various agents, for example, 12-O-tetradecanoylphorbol 13-acetate, N-4-hydroxy-phenyl-retinamide and arsenic trioxide. However, the molecular mechanisms underlying how JWA gene is functionally involved in apoptosis remain largely unknown. Herein, our studies demonstrated that treatment of arsenic trioxide produced apoptosis in HeLa and MCF-7 cells in a dose-dependent manner and paralleled with increased JWA expression. JWA expression was dependent upon generation of intracellular reactive oxygen species induced by arsenic trioxide. Knockdown of JWA attenuated arsenic trioxide induced apoptosis, and was accompanied by significantly reduced activity of caspase-9, enhanced Bad phosphorylation and inhibited MEK1/2, ERK1/2 and JNK phosphorylations. Arsenic trioxide induced loss of mitochondrial transmembrane potential was JWA-dependent. These findings suggest that JWA may serve as a pro-apoptotic molecule to mediate arsenic trioxide triggered apoptosis via a reactive oxygen species and mitochondria-associated signal pathway.
三氧化二砷作为难治性急性早幼粒细胞白血病的标准治疗药物，可诱导多种恶性细胞系发生凋亡。JWA是一种新型视黄酸诱导基因，已知其参与多种药物诱导的凋亡过程，例如12-O-十四酰佛波醇-13-乙酸酯、N-4-羟基苯基视黄酰胺和三氧化二砷。然而，JWA基因在功能上如何参与凋亡的分子机制仍 largely未知。在此，我们的研究表明，三氧化二砷处理以剂量依赖的方式诱导HeLa和MCF-7细胞凋亡，且与JWA表达增加平行。JWA表达依赖于三氧化二砷诱导的细胞内活性氧的产生。敲低JWA可减弱三氧化二砷诱导的凋亡，并伴有caspase-9活性显著降低、Bad磷酸化增强以及MEK1/2、ERK1/2和JNK磷酸化受到抑制。三氧化二砷诱导的线粒体跨膜电位丧失是JWA依赖性的。这些发现表明，JWA可能作为一种促凋亡分子，通过活性氧和线粒体相关信号通路介导三氧化二砷触发的凋亡。
