Dasatinib promotes paclitaxel-induced necroptosis in lung adenocarcinoma with phosphorylated caspase-8 by c-Src
Dasatinib promotes paclitaxel-induced necroptosis in lung adenocarcinoma with phosphorylated caspase-8 by c-Src
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达沙替尼通过 c-Src 磷酸化 caspase-8 促进紫杉醇诱导的肺腺癌坏死性凋亡
DOI：
10.1016/j.canlet.2016.05.003
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发表时间：
2016-08-28
期刊：
影响因子：
9.7
通讯作者：
Zhao, Yang
中科院分区：
文献类型：
--
作者：
Diao, Yan;Ma, Xiaobin;Zhao, Yang
顺铂和紫杉醇被认为是肺腺癌化疗的支柱。这些药剂对细胞死亡显示出多效性作用。然而，确切的机制仍不清楚。本研究报道了磷酸化caspase-8酪氨酸380（p-Casp 8）是TP方案（顺铂和紫杉醇）化疗耐药的生物标志物，可切除肺腺癌患者的5年无病生存期（DFS）和总生存期（OS）明显较差。顺铂杀死肺腺癌细胞，而不管c-Src诱导的caspase-8在酪氨酸380磷酸化。随后，我们确定了紫杉醇诱导肺腺癌细胞坏死性凋亡的一种新机制，该机制依赖于p-Casp 8、受体相互作用蛋白激酶1（RIPK 1）和RIPK 3。此外，达沙替尼，一种c-Src抑制剂，去磷酸化caspase-8，以促进坏死性凋亡，而不是凋亡，在紫杉醇处理的p-Casp 8表达肺腺癌细胞。我们研究的数据揭示了p-Casp 8之前未被认识到的作用，即在坏死性凋亡的启动中作为阳性效应子，以及在抑制RIPK 1和RIPK 3之间相互作用中作为阴性效应子。此外，这些结果支持需要进一步的临床研究，以评估达沙替尼联合紫杉醇治疗肺腺癌的疗效。(C)2016爱思唯尔爱尔兰有限公司版权所有。
Cisplatin and paclitaxel are considered to be the backbone of chemotherapy in lung adenocarcinoma. These agents show pleiotropic effects on cell death. However, the precise mechanisms remain unclear. The present study reported that phosphorylated caspase-8 at tyrosine 380 (p-Casp8) was characterized as a biomarker of chemoresistance to TP regimen (cisplatin and paclitaxel) in patients with resectable lung adenocarcinoma with significantly poorer 5-year disease-free survival (DFS) and overall survival (OS). Cisplatin killed lung adenocarcinoma cells regardless of c-Src-induced caspase-8 phosphorylation at tyrosine 380. Subsequently, we identified a novel mechanism by which paclitaxel induced necroptosis in lung adenocarcinoma cells that was dependent upon p-Casp8, receptor-interacting protein kinase 1 (RIPK1), and RIPK3. Moreover, dasatinib, a c-Src inhibitor, dephosphorylated caspase-8 to facilitate necroptosis, rather than apoptosis, in paclitaxel-treated p-Casp8-expressing lung adenocarcinoma cells. The data from our study revealed previously unrecognized roles of p-Casp8 as a positive effector in the initiation of necroptosis and as a negative effector in the repression of the interaction between RIPK1 and RIPK3. Moreover, these outcomes supported the need for further clinical studies with the goal of evaluating the efficacy of dasatinib plus paclitaxel in the treatment of lung adenocarcinoma. (C) 2016 Elsevier Ireland Ltd. All rights reserved.