title: Dasatinib promotes paclitaxel-induced necroptosis in lung adenocarcinoma with phosphorylated caspase-8 by c-Src.
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.
authors.affiliation: Department of Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province 710004, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Diao
authors.affiliation: Department of Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province 710004, China.
authors.forename: Xiaobin
authors.initials: X
authors.lastname: Ma
authors.affiliation: Department of Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province 710004, China.
authors.forename: WeiLi
authors.initials: W
authors.lastname: Min
authors.affiliation: Department of Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province 710004, China.
authors.forename: Shuai
authors.initials: S
authors.lastname: Lin
authors.affiliation: Department of Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province 710004, China.
authors.forename: HuaFeng
authors.initials: H
authors.lastname: Kang
authors.affiliation: Department of Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province 710004, China.
authors.forename: ZhiJun
authors.initials: Z
authors.lastname: Dai
authors.affiliation: Department of Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province 710004, China.
authors.forename: Xijing
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province 710004, China. Electronic address: szhaoy@126.com.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhao
mesh_terms: D000072283:A549 Cells; D000230:Adenocarcinoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism*; D002945:Cisplatin / Q000494:pharmacology; D000069439:Dasatinib / Q000494:pharmacology*; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D009336:Necrosis; D017239:Paclitaxel / Q000494:pharmacology* / Q000627:therapeutic use; D010766:Phosphorylation; D011247:Pregnancy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014162:Transfection; D016896:Treatment Outcome; D014443:Tyrosine; D023041:Xenograft Model Antitumor Assays
chemical_list: D047428:Protein Kinase Inhibitors; D014443:Tyrosine; D016392:Proto-Oncogene Proteins pp60(c-src); C506249:RIPK1 protein, human; C119705:RIPK3 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C505530:CASP8 protein, human; D053181:Caspase 8; D017239:Paclitaxel; D002945:Cisplatin; D000069439:Dasatinib
keywords: Dasatinib; Lung adenocarcinoma; Necroptosis; Paclitaxel