Essential role of caspase-8 in p53/p73-dependent apoptosis induced by etoposide in head and neck carcinoma cells.
Essential role of caspase-8 in p53/p73-dependent apoptosis induced by etoposide in head and neck carcinoma cells.
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DOI：
10.1186/1476-4598-10-95
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发表时间：
2011-07-31
期刊：
影响因子：
37.3
通讯作者：
Ikeda MA
中科院分区：
文献类型：
--
作者：
Liu J;Uematsu H;Tsuchida N;Ikeda MA
Caspase-8是死亡受体介导的细胞凋亡中的关键上游介质，并且还通过切割促凋亡的Bid参与Escherichia介导的细胞凋亡。然而，caspase-8在基因毒性药物诱导的p53和p73依赖性细胞凋亡中的作用仍不清楚。我们最近报道，在化疗耐药和caspase-8缺陷的HOC 313头颈部鳞状细胞癌（HNSCC）细胞中，caspase-8的重建足以敏化顺铂诱导的凋亡，但不能敏化依托泊苷诱导的凋亡。我们发现，p53/p73依赖性caspase-8激活所需的敏感依托泊苷诱导的凋亡，利用HOC 313细胞携带温度敏感的p53 G285 K突变体。在允许的条件下恢复野生型p53的功能，与依托泊苷治疗，导致大量的转录激活的促凋亡Noxa和NoxA，但未能诱导细胞凋亡。除了p53的恢复，caspase-8的重建是需要的敏感依托泊苷诱导的细胞凋亡，线粒体去极化，和切割的前半胱氨酸蛋白酶-3，9。在携带温度不敏感突变体p53的依托泊苷敏感的Ca 9 -22细胞中，基于siRNA的p73敲低阻断依托泊苷诱导的凋亡和半胱氨酸天冬氨酸蛋白酶原-8切割。然而，尽管在Ca 9 -22细胞中观察到p73蛋白的诱导以及Noxa和NoxA的上调，但在非允许条件下在依托泊苷处理的HOC 313细胞中几乎未检测到，这表明HOC 313细胞中p73减少对依托泊苷抗性的贡献。最后，caspase-9抑制剂Ac-LEHD-CHO或caspase-9 siRNA阻断了两种细胞系中依托泊苷诱导的caspase-8活化、Bid裂解和凋亡，表明p53/p73依赖性caspase-8活化位于线粒体下游。p53和p73可能是caspase-8的上游调控因子，caspase-8是依托泊苷诱导HNSCC细胞凋亡的重要介质。我们的数据表明caspase-8介导的正反馈放大在依托泊苷诱导的HNSCC细胞p53/p73依赖性凋亡中的重要性。
Caspase-8 is a key upstream mediator in death receptor-mediated apoptosis and also participates in mitochondria-mediated apoptosis via cleavage of proapoptotic Bid. However, the role of caspase-8 in p53- and p73-dependent apoptosis induced by genotoxic drugs remains unclear. We recently reported that the reconstitution of procaspase-8 is sufficient for sensitizing cisplatin- but not etoposide-induced apoptosis, in chemoresistant and caspase-8 deficient HOC313 head and neck squamous cell carcinoma (HNSCC) cells. We show that p53/p73-dependent caspase-8 activation is required for sensitizing etoposide-induced apoptosis by utilizing HOC313 cells carrying a temperature-sensitive p53G285K mutant. Restoration of wild-type p53 function under the permissive conditions, together with etoposide treatment, led to substantial transcriptional activation of proapoptotic Noxa and PUMA, but failed to induce apoptosis. In addition to p53 restoration, caspase-8 reconstitution was needed for sensitization to etoposide-induced apoptosis, mitochondria depolarization, and cleavage of the procaspases-3, and -9. In etoposide-sensitive Ca9-22 cells carrying a temperature-insensitive mutant p53, siRNA-based p73 knockdown blocked etoposide-induced apoptosis and procaspase-8 cleavage. However, induction of p73 protein and up-regulation of Noxa and PUMA, although observed in Ca9-22 cells, were hardly detected in etoposide-treated HOC313 cells under non-permissive conditions, suggesting a contribution of p73 reduction to etoposide resistance in HOC313 cells. Finally, the caspase-9 inhibitor Ac-LEHD-CHO or caspase-9 siRNA blocked etoposide-induced caspase-8 activation, Bid cleavage, and apoptosis in both cell lines, indicating that p53/p73-dependent caspase-8 activation lies downstream of mitochondria. we conclude that p53 and p73 can act as upstream regulators of caspase-8, and that caspase-8 is an essential mediator of the p53/p73-dependent apoptosis induced by etoposide in HNSCC cells. Our data suggest the importance of caspase-8-mediated positive feedback amplification in the p53/p73-dependent apoptosis induced by etoposide in HNSCC cells.
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影响因子：
4.8
作者：
Bossy-Wetzel, E;Green, DR
通讯作者：
Green, DR
影响因子：
4.3
作者：
Biswas, RS;Cha, HJ;Srivastava, RK
通讯作者：
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影响因子：
8
作者：
Fulda, S;Meyer, E;Debatin, KM
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DOI：
10.1016/j.bbrc.2009.10.090
发表时间：
2009-12-18
影响因子：
3.1
作者：
Liu, Juan;Uematsu, Hiroshi;Ikeda, Masa-Aki
通讯作者：
Ikeda, Masa-Aki
DOI：
10.1073/pnas.94.15.8144
发表时间：
1997-07-22
影响因子：
11.1
作者：
Houghton, JA;Harwood, FG;Tillman, DM
通讯作者：
Tillman, DM