Dasatinib promotes paclitaxel-induced necroptosis in lung adenocarcinoma with phosphorylated caspase-8 by c-Src. Issue 1 (28th August 2016)

• Record Type: Journal Article
• Authors: Diao, Yan; Ma, Xiaobin; Min, WeiLi; Lin, Shuai; Kang, HuaFeng; Dai, ZhiJun; Wang, Xijing; Zhao, Yang
• Is Part Of: Cancer letters. Volume 379:Issue 1(2016)
• Page Start: 12
• Page End: 23
• Publication Date: 2016-08-28
• Subjects: Paclitaxel -- Dasatinib -- Necroptosis -- Lung adenocarcinoma; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2016.05.003
• Languages: English
• ISSNs: 0304-3835

Abstract

Highlights: Phosphorylated caspase-8 by c-Src indicated lower response rate to TP regimen in patients with lung adenocarcinoma. Paclitaxel induced necroptosis in lung adenocarcinoma cells dependently of c-Src-phosphorylated caspase-8, RIPK1 and RIPK3. c-Src inhibitor dephosphorylated caspase-8 to promote necroptosis in the paclitaxel-treated Casp8 + Src + cells. Abstract: 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.