Effect of Bax deficiency on death receptor 5 and mitochondrial pathways during endoplasmic reticulum calcium pool depletion-induced apoptosis
Effect of Bax deficiency on death receptor 5 and mitochondrial pathways during endoplasmic reticulum calcium pool depletion-induced apoptosis
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DOI：
10.1038/sj.onc.1206363
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发表时间：
2003-05-01
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;Montalbano, J;Sheikh, MS
Thapsigargin (TG) 通过扰动细胞 Ca2+ 稳态，可以诱导细胞凋亡，但其分子机制仍有待充分阐明。我们最近报道，TG 诱导的细胞凋亡似乎涉及 DR5 依赖性细胞凋亡途径，该途径通过 TG 诱导的 Bid 裂解与线粒体途径相互作用。在本研究中，我们利用 Bax 丰富和缺陷的 HCT116 人结肠癌细胞来研究 Bax 缺陷对 TG 诱导的细胞凋亡以及 DR5 和线粒体途径的 TG 调节的影响。我们的结果表明，Bax 缺陷细胞在 TG 处理后对细胞凋亡不太敏感。我们的结果进一步证明，TG 诱导的细胞凋亡与 DR5 上调和 caspase 8 和 3 激活以及 Bax 充足和缺陷细胞中的 Bid 裂解相结合，尽管在 Bax 缺陷细胞中 caspase 3 激活减少。 TG 还促进细胞色素 c 释放到细胞质中，并在 Bax 熟练的细胞中促进 caspase 9 激活，但在 Bax 缺陷的细胞中则不然。这些发现表明，尽管 Bax 并不是死亡受体 (DR) 依赖性信号所必需的，但它似乎是 TG 调节的线粒体事件中的关键分子。 Bax 缺陷的细胞比 Bax 充分的细胞对 Apo2L/TRAIL 的抵抗力相对更强。然而，Apo2L/TRAIL 和 TG 的组合在介导 Bax 熟练的细胞凋亡方面更有效。和 - 缺陷细胞，并且与 caspase 8 和 3 的激活相结合。尽管两种药物组合也诱导细胞色素 c 释放到细胞质中，并在 Bax 熟练细胞中诱导 caspase 9 激活，但这些事件在 Bax 缺陷细胞中被消除。因此，我们的结果表明，Apo2L/TRAIL 和 TG 的组合似乎通过参与 DR5 依赖性细胞凋亡信号（外在途径）来绕过 Bax 缺陷引起的线粒体（内在）途径缺陷。
Thapsigargin (TG), by inducing perturbations in cellular Ca2+ homeostasis, can induce apoptosis, but the molecular mechanisms remain to be fully elucidated. We have recently reported that TG-induced apoptosis appears to involve the DR5-dependent apoptotic pathway that cross talks with the mitochondrial pathway via TG-induced Bid cleavage. In this study, we have utilized Bax-proficient and -deficient HCT116 human colon cancer cells to investigate the effect of Bax deficiency on TG-induced apoptosis and TG regulation of the DR5 and mitochondrial pathways. Our results indicate that Bax-deficient cells are less sensitive to undergo apoptosis following TG treatment. Our results further demonstrate that TG-induced apoptosis is coupled with DR5 upregulation and caspases 8 and 3 activation, as well as Bid cleavage in both Bax-proficient and -deficient cells, although caspase 3 activation was reduced in Bax-deficient cells. TG also promoted the release of cytochrome c into cytosol and caspase 9 activation in Bax-proficient cells but not in Bax-deficient cells. These findings suggest that although Bax is not absolutely required for death receptor (DR)-dependent signals, it appears to be a key molecule in TG-regulated mitochondrial events. Bax-deficient cells were relatively more resistant to Apo2L/TRAIL than the Bax-proficient counterparts. However, the combination of Apo2L/TRAIL and TG was more effective in mediating apoptosis in both Bax-proficient. and -deficient cells and that was coupled with activation of caspases 8 and 3. Although both agents in combination also induced cytochrome c release into cytosol and caspase 9 activation in Bax-proficient cells, these events were abrogated in Bax-deficient cells. Our results thus suggest that the combination of Apo2L/TRAIL and TG appears to bypass the Bax deficiency-induced defects in the mitochondrial (intrinsic) pathway by engaging the DR5-dependent apoptotic signals (extrinsic pathway).