Endoplasmic reticulum calcium pool depletion-induced apoptosis is coupled with activation of the death receptor 5 pathway
Endoplasmic reticulum calcium pool depletion-induced apoptosis is coupled with activation of the death receptor 5 pathway
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DOI：
10.1038/sj.onc.1205345
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发表时间：
2002-04-18
期刊：
影响因子：
8
通讯作者：
Sheikh, MS
中科院分区：
文献类型：
--
作者：
He, Q;Lee, DI;Sheikh, MS
毒胡萝卜素（TG），通过诱导细胞内钙稳态的扰动，已被证明可以诱导细胞凋亡。Ca 2+扰动诱导细胞凋亡的分子机制尚未完全了解。在这项研究中，我们首次证明了TG介导的Ca 2+稳态扰动与人类癌细胞中死亡受体5（DR 5）依赖性凋亡途径的激活相结合。TG选择性上调DR 5，但对另一个TRAIL受体DR 4的表达没有影响。TG还上调DR 5配体TRAIL（肿瘤坏死因子相关凋亡诱导配体）的表达，尽管是以细胞类型特异性的方式。TG诱导的细胞凋亡已被证明与线粒体途径的激活有关。我们发现TG上调DR 5和TRAIL与半胱天冬酶8激活和BID切割相结合，这表明TG调节的DR 5途径可能与线粒体途径有关。TG不仅增强DR 5 mRNA的稳定性，而且增加DR 5基因组启动子-报告基因的诱导。TG诱导的DR 5表达增加似乎是TG诱导的内质网（ER）Ca 2+池耗竭的结果。因此，我们报告了我们的新发现，ER Ca 2+池耗竭诱导的凋亡信号介导，至少部分，通过DR 5依赖性凋亡途径，似乎是死亡受体和线粒体途径之间的串扰。
Thapsigargin (TG), by inducing perturbations in cellular Ca2+ homeostasis, has been shown to induce apoptosis. The molecular mechanisms of Ca2+ perturbation-induced apoptosis are not fully understood. In this study, we demonstrate for the first time that TG-mediated perturbations in Ca2+ homeostasis are coupled with activation of the death receptor 5 (DR5)-dependent apoptotic pathway in human cancer cells. TG selectively upregulated DR5 but had no effect on the expression 4 the other TRAIL receptor, DR4. TG also upregulated the expression of the DR5 ligand TRAIL (tumor necrosis factor-related apoptosis inducing ligand), albeit in a cell-type specific manner. TG-induced apoptosis has been shown to be associated with activation of the mitochondrial pathway. We found that TG upregulation of DR5 and TRAIL was coupled with caspase 8 activation and Bid cleavage, suggesting that the TG-regulated DR5 pathway could be linked to the mitochondrial pathway. TG enhanced not only DR5 mRNA stability but also increased induction of the DR5 genomic promoter-reporter gene. The TG-induced increase in DR5 expression appeared to occur as a consequence of TG-induced endoplasmic reticulum (ER) Ca2+ pool depletion. Thus, we report our novel findings that ER Ca2+ pool depletion-induced apoptotic signals are mediated, at least in part, via a DR5-dependent apoptotic pathway and there appears to be a cross-talk between the death receptor and mitochondrial pathways.