EMT confers increased metastatic potential and the resistance to
chemotherapies to
cancer cells. However, the precise mechanisms of EMT-related
chemotherapy resistance remain unclear. c-Src-mediated
caspase 8 phosphorylation essential for EMT in
lung adenocarcinoma cell lines preferentially occurs in cells with the mesenchymal phenotype, resulting in chemoresistance to
cisplatin plus
paclitaxel in patients with resectable
lung adenocarcinoma and a significantly worse 5-year PFS.
Cisplatin killed
lung adenocarcinoma cells regardless of
caspase 8.
Paclitaxel-triggered necroptosis in
lung adenocarcinoma cells was dependent on the phosphorylation or deficiency of
caspase 8, during which FADD interacted with RIPK1 to activate the RIPK1/RIPK3/MLKL signaling axis. Accompanied with c-Src-mediated
caspase 8 phosphorylation to trigger EMT, a novel
lncRNA named lncCRLA was markedly upregulated and inhibited RIPK1-induced necroptosis by impairing RIPK1RIPK3 interaction via binding to the intermediate domain of RIPK1.
Dasatinib mitigated c-Src-mediated phosphorylation of
caspase 8-induced EMT and enhanced necroptosis in mesenchymal-like
lung adenocarcinoma cells treated with
paclitaxel, while c-FLIP knockdown predominantly sensitized the mesenchymal-like
lung adenocarcinoma cells to paclitaxel+dasatinib. c-Srccaspase 8 interaction initiates EMT and chemoresistance via
caspase 8 phosphorylation and lncCRLA expression, to which the
dasatinib/
paclitaxel liposome+siFLIP regimen was lethal.