Mechanism of staurosporine-induced apoptosis in murine hepatocytes
Mechanism of staurosporine-induced apoptosis in murine hepatocytes
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DOI：
10.1152/ajpgi.00467.2001
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发表时间：
2002-05-01
影响因子：
4.5
通讯作者：
Kaplowitz, N
中科院分区：
文献类型：
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作者：
Feng, GP;Kaplowitz, N
星形孢菌素（STS）在多种细胞系中诱导凋亡。我们在这项研究中报告，原代培养的小鼠肝细胞与Jurkat细胞和Huh-7细胞相比，对STS的敏感性较低。在相反的细胞系，没有明显的细胞色素c的释放或线粒体跨膜电位的损失进行STS诱导的细胞凋亡的原代肝细胞检测。STS处理可激活原代肝细胞中的Caspase-3，但caspase-9和-12未被激活，caspase-3的激活不依赖于caspase-8。这些发现指出了STS在原代肝细胞中激活caspase-3的新途径。半胱天冬酶抑制剂预处理STS诱导的肝细胞凋亡转化为坏死性细胞死亡，而不显着改变总细胞死亡。因此，STS导致肝细胞在半胱天冬酶激活的上游死亡。我们还证实STS对肿瘤坏死因子-α诱导的细胞凋亡显著敏感原代肝细胞。STS激活IkappaB激酶和核因子-κ B（NF-κ B）核转位和DNA结合，但抑制IkappaB-α、诱导型一氧化氮合酶和肝细胞凋亡抑制蛋白-1和转染Huh-7细胞中NF-κ B报告基因的反式激活。
Staurosporine (STS) induces apoptosis in various cell lines. We report in this study that primary cultured mouse hepatocytes are less sensitive to STS compared with Jurkat cells and Huh-7 cells. In contrast to the cell lines, no apparent release of cytochrome c or loss of mitochondrial transmembrane potential was detected in primary hepatocytes undergoing STS-induced apoptosis. Caspase-3 was activated in primary hepatocytes by STS treatment, but caspase-9 and -12 were not activated, and caspase-3 activation is not dependent on caspase-8. These findings point to a novel pathway for caspase-3 activation by STS in primary hepatocytes. Pretreatment with caspase inhibitor converted STS-induced apoptosis of hepatocytes to necrotic cell death without significantly changing total cell death. Thus STS causes hepatocytes to commit to death upstream of the activation of caspases. We also demonstrated that STS dramatically sensitized primary hepatocytes to tumor necrosis factor-alpha-induced apoptosis. STS activated IkappaB kinase and nuclear factor-kappaB (NF-kappaB) nuclear translocation and DNA binding but inhibited transactivation of IkappaB-alpha, inducible nitric oxide synthase, and inhibitor of apoptosis protein-1 in hepatocytes and NF-kappaB reporter in transfected Huh-7 cells.