Zheng Yanhua, Yamaguchi Hirohito, Tian Changhai, Lee Michael W, Tang Hong, Wang Hong-Gang, Chen Quan
The Laboratory of Apoptosis and Cancer Biology, The National Key Laboratory of Biomembrane and Membrane Biotechnology, The Institute of Zoology, Chinese Academy of Sciences, Beijing 100080, People's Republic of China.
Oncogene. 2005 May 5;24(20):3339-47. doi: 10.1038/sj.onc.1208484.
This study explores the roles of Bax and other Bcl-2 family members play in arsenic trioxide (As(2)O(3))-induced apoptosis. We showed that As(2)O(3) treatment triggered Bax conformational change and subsequent translocation from cytosol to mitochondria to form various multimeric homo-oligomers in IM-9 cells. On the other hand, human leukemic Jurkat cells deficient in Bax showed dramatically reduced apoptosis in response to As(2)O(3). Stable overexpression of Bcl-2 in IM-9 cells (IM-9/Bcl-2) inhibited As(2)O(3)-mediated Bax activation and apoptosis, and this inhibition could be partially averted by cell-permeable Bid-Bcl-2 homology (BH)3 peptide. Meanwhile, Bax conformational change and oligomerization induced by As(2)O(3) were not inhibited by the pancaspase inhibitor z-VAD-fmk, although Bid cleavage could be completely abolished. Bax activation by As(2)O(3) seemed to require stress-induced intracellular reactive oxygen species (ROS), since the ROS scavengers (N-acetyl-L-cysteine and lipoic acid) could completely block the conformational change and translocation of Bax from cytosol to mitochondria. These data suggest that As(2)O(3) might exert the cell killing in part by inducing Bax activation through a Bcl-2-suppressible pathway in hematopoietic cells that is caspase independent and intracellular ROS regulated.
本研究探讨了Bax及其他Bcl-2家族成员在三氧化二砷（As₂O₃）诱导的细胞凋亡中所起的作用。我们发现，As₂O₃处理可引发IM-9细胞中Bax的构象变化，并随后从细胞质转位至线粒体，从而形成各种多聚体同源寡聚体。另一方面，缺乏Bax的人白血病Jurkat细胞对As₂O₃的反应显示出显著降低的细胞凋亡。在IM-9细胞（IM-9/Bcl-2）中稳定过表达Bcl-2可抑制As₂O₃介导的Bax激活和细胞凋亡，而细胞可渗透的Bid-Bcl-2同源（BH）3肽可部分消除这种抑制作用。同时，尽管Bid裂解可被完全消除，但As₂O₃诱导的Bax构象变化和寡聚化不受泛半胱天冬酶抑制剂z-VAD-fmk的抑制。As₂O₃对Bax的激活似乎需要应激诱导的细胞内活性氧（ROS），因为ROS清除剂（N-乙酰-L-半胱氨酸和硫辛酸）可完全阻断Bax从细胞质到线粒体的构象变化和转位。这些数据表明，As₂O₃可能部分通过在造血细胞中通过一种Bcl-2可抑制的途径诱导Bax激活来发挥细胞杀伤作用，该途径不依赖于半胱天冬酶且受细胞内ROS调节。
