Dasatinib promotes paclitaxel-induced necroptosis in lung adenocarcinoma with phosphorylated caspase-8 by c-src

• Published in: Cancer letters 2016-08, Vol.379 (1), p.12-23
• Main Authors: Diao, Yan, Ma, Xiaobin, Min, Weili, M.D, Lin, Shuai, Kang, HuaFeng, M.D, Dai, Zhijun, Ph.D, Wang, Xijing, M.D, Zhao, Yang
• Format: Article
• Language: English
• Subjects: A549 Cells; Adenocarcinoma - drug therapy; Adenocarcinoma - enzymology; Adenocarcinoma - genetics; Adenocarcinoma - pathology; Adenocarcinoma of Lung; Animals; Antigens; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Apoptosis; Apoptosis - drug effects; Cancer therapies; Caspase 8 - genetics; Caspase 8 - metabolism; Chemotherapy; Cisplatin - pharmacology; Dasatinib; Dasatinib - pharmacology; Disease-Free Survival; Drug Resistance, Neoplasm - drug effects; Female; Hematology, Oncology and Palliative Medicine; Humans; Immunoglobulins; Kaplan-Meier Estimate; Kinases; Lung adenocarcinoma; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - enzymology; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Male; Metastasis; Mice, Inbred BALB C; Mice, Nude; Middle Aged; Necroptosis; Necrosis; Paclitaxel; Paclitaxel - pharmacology; Paclitaxel - therapeutic use; Phosphorylation; Pregnancy; Protein Kinase Inhibitors - pharmacology; Proteins; Proto-Oncogene Proteins pp60(c-src) - antagonists & inhibitors; Proto-Oncogene Proteins pp60(c-src) - genetics; Proto-Oncogene Proteins pp60(c-src) - metabolism; Receptor-Interacting Protein Serine-Threonine Kinases - genetics; Receptor-Interacting Protein Serine-Threonine Kinases - metabolism; RNA Interference; Signal Transduction - drug effects; Time Factors; Transfection; Treatment Outcome; Tumors; Tyrosine; Xenograft Model Antitumor Assays
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2016.05.003

The Highlights of Our Study • Phosphoryalted caspase-8 by c-Src was screened out by protein microarray to predict the poorer disease-free and overall survival with lower response rate to TP regimen in patients with lung adenocarcinoma. • We displayed a novelty mechanism by which paclitaxel induced necroptosis in lung adenocarcinoma cells dependently of c-Src-phosphorylated caspase-8 at 380 tyrosine (p-Casp8), receptor-interacting protein kinase 1 (RIPK1) and RIPK3. • Dasatinib, c-Src inhibitor, dephosphorylated caspase-8 to give rise to the enhancement of necroptosis in the paclitaxel-treated Casp8+ Src+ lung adenocarcinoma cells.