Open Access

ARTICLE

lncCRLA Enhanced Chemoresistance in Lung Adenocarcinoma That Underwent Epithelial–Mesenchymal Transition

Weili Min^*1, Liangzhang Sun^†1, Burong Li^‡, Xiao Gao^*, Shuqun Zhang^*, Yang Zhao^*

* Department of Oncology, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, P.R. China
† Thoracic Department, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, P.R. China
‡ Department of Clinical Laboratory, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, P.R. China

Oncology Research 2020, 28(9), 857-872. https://doi.org/10.3727/096504021X16203818567367

Abstract

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 RIPK1– RIPK3 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-Src–caspase 8 interaction initiates EMT and chemoresistance via caspase 8 phosphorylation and lncCRLA expression, to which the dasatinib/paclitaxel liposome + siFLIP regimen was lethal.

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Keywords

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