Caspase-8-mediated intracellular acidification precedes mitochondrial dysfunction in somatostatin-induced apoptosis
Caspase-8-mediated intracellular acidification precedes mitochondrial dysfunction in somatostatin-induced apoptosis
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DOI：
10.1074/jbc.275.13.9244
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发表时间：
2000-03-31
影响因子：
4.8
通讯作者：
Srikant, CB
中科院分区：
文献类型：
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作者：
Liu, D;Martino, G;Srikant, CB
启动子和效应子半胱天冬酶的激活、线粒体膜电位的降低和细胞色素c（cyt c）释放到胞浆中是细胞凋亡的特征。这些变化在某些细胞凋亡模型中与细胞酸化有关。我们发现生长抑素（SST）通过Src同源2酪氨酸磷酸酶SHP-1发挥作用，在MCF-7细胞中发挥细胞毒性作用，并触发细胞酸化和凋亡。我们研究了凋亡事件的时间顺序，和线粒体功能障碍，并在此报道（i）SST诱导的pH降低需要SHP-1介导的半胱天冬酶-8活化（i），（ii）只有在伴随酸化时才诱导效应半胱天冬酶。(iii)pH的降低是诱导线粒体膜电位降低、cyt c释放和半胱天冬酶-9活化所必需的，并且（iv）ATP的消耗消除SST诱导的cyt c释放和半胱天冬酶-9活化，但不消除其诱导效应半胱天冬酶和凋亡的能力，这些数据表明，SHP-1-/caspase-8介导的酸化发生在除线粒体以外的位点，SST-1-/caspase-8介导的酸化发生在线粒体以外的位点。诱导的细胞凋亡不依赖于线粒体功能的破坏和半胱天冬酶-9的活化。
Activation of initiator and effector caspases, mitochondrial changes involving a reduction in its membrane potential and release of cytochrome c (cyt c) into the cytosol, are characteristic features of apoptosis, These changes are associated with cell acidification in some models of apoptosis, The hierarchical relationship between these events has, however, not been deciphered. We have shown that somatostatin (SST), acting via the Src homology 2 bearing tyrosine phosphatase SHP-1, exerts cytotoxic action in MCF-7 cells, and triggers cell acidification and apoptosis, We investigated the temporal sequence of apoptotic events linking caspase activation, acidification, and mitochondrial dysfunction in this system and report here that (i) SHP-1-mediated caspase-8 activation is required for SST-induced decrease in pH(i), (ii) Effector caspases are induced only when there is concomitant acidification. (iii) Decrease in pH, is necessary to induce reduction in mitochondrial membrane potential, cyt c release and caspase-9 activation and (iv) depletion of ATP ablates SST-induced cyt c release and caspase-9 activation, but not its ability to induce effector caspases and apoptosis, These data reveal that SHP-1-/caspase-8-mediated acidification occurs at a site other than the mitochondrion and that SST-induced apoptosis is not dependent on disruption of mitochondrial function and caspase-9 activation.