Molecular mechanism of glucocorticoid-induced apoptosis

糖皮质激素（GC）用于治疗白血病或淋巴瘤，因为GC可诱导某些类型的淋巴细胞凋亡。然而，GC介导细胞凋亡的机制尚不清楚。本研究旨在阐明gc介导细胞凋亡的分子机制。在两年的时间里，我们使用b前白血病细胞系697获得了以下结果：在gc介导的细胞凋亡过程中，线粒体膜电位和活性氧产生减少。这两者以及细胞死亡本身都被一种泛caspase抑制剂zad -fmk.2所抑制。另一方面，caspase-3样蛋白酶抑制剂AC-DEVD-CHO对两者均无抑制作用，但能显著抑制DNA片段化。这些结果表明，在线粒体变化的上游存在caspase(s)，该酶可被zVAD-fmk抑制，而不受AC-DEVD-CHO的抑制。出乎意料的是，在gc诱导的细胞凋亡过程中，主要的效应caspase-3并没有被蛋白水解激活。相反，caspase-6和-7，其他效应caspase，被加工和激活。这些结果表明，GC触发的细胞凋亡具有不同的途径，其中不涉及caspase-3。

Glucocorticoid (GC) is used for the treatment of leukemias or lymphomas because GC induces apoptosis in certain types of lymphocytes. However, the mechanism of how GC mediates apoptosis is unknown. The purpose of this research project was to elucidate the molecular mechanism of GC-mediated apoptosis. During the period of two years we got the results as follows using 697, a pre-B leukemia cell line.1. Reduction of mitochondrial membrane potential and reactive oxygen production were observed during GC-mediated apoptosis. Both of which, as well as cell death itself were inhibited by a pan-caspase inhibitor, zVAD-fmk.2. On the other hand, a caspase-3-like protease inhibitor, AC-DEVD-CHO inhibited neither of them, while significantly inhibited DNA fragmentation.3.These results indicate the presence of caspase(s), which is inhibited by zVAD-fmk but not by AC-DEVD-CHO, upstream of mitochondrial changes.4.Unexpectedly, caspase-3, a main effector caspase, was not proteolytically activated during GC-induced apoptosis.5. Instead, caspase-6 and -7, other effector caspases, were processed and activated.6. These results indicate that apoptosis triggered by GC has a distinct pathway where caspase-3 is not involved.