lncCRLA Enhanced Chemoresistance in Lung Adenocarcinoma That Underwentepithelial-mesenchymal Transition

Abstract BackgroundEMT confers increased metastatic potential andtheresistance to chemotherapiesto cancer cells.However, the precise mechanisms of EMT-related chemotherapy resistance remain unclear.MethodsAnticancer effects were determined by MTT, soft agar, cell cycle, propidium iodide and Annexin V analysis. The effect of drugs on tumor growth was assessed using patient-derived xenograft model and nude mice model.Morphology of tumor cells were observed by phase contrast microscopy. Proteins interactions were tested by western blot and coimmunoprecipitation. Immunohistochemistry and LNA ISH were performed to determine protein and lncRNA expression. Candidate lncRNA was screened out by microarray.Resultsc-Src-mediated Caspase-8 phosphorylationessential for EMT in lung adenocarcinoma cell linespreferentially occurs in cells with themesenchymal phenotype,resultingin chemoresistance tocisplatin plus paclitaxel in patients with resectable lung adenocarcinoma and a significantly worse5-yearPFS. Cisplatin killedlung adenocarcinoma cells regardless of Caspase-8. Paclitaxel-triggered necroptosis in lung adenocarcinoma cells was dependent on the phosphorylation or deficiency ofCaspase-8, during which FADDinteracted with RIPK1 to activateRIPK1/RIPK3/MLKL signaling axis. Accompanied with c-Src-mediated Caspase-8 phosphorylation to trigger EMT, a novel lncRNA named lncCRLA was markedly upregulated andinhibited RIPK1-induced necroptosis byimpairingRIPK1-RIPK3 interaction via binding to the intermediate domain of RIPK1. Dasatinibmitigatedc-Src-mediated phosphorylationof 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.Conclusionsc-Src-Caspase-8 interaction initiatesEMT and chemoresistance viaCaspase-8 phosphorylation and lncCRLA expression, to which the dasatinib/paclitaxel liposome+siFLIPregimen was lethal.

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lncCRLA enhanced chemoresistance in lung adenocarcinoma that underwent epithelial-mesenchymal transition

Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics ◽

10.3727/096504021x16203818567367 ◽

2021 ◽

Author(s):

Weili Min ◽

Liangzhang Sun ◽

Burong Li ◽

Xiao Gao ◽

Shuqun Zhang ◽

...

Keyword(s):

Lung Adenocarcinoma ◽

Epithelial Mesenchymal Transition ◽

Chemotherapy Resistance ◽

Metastatic Potential ◽

Caspase 8 ◽

Mesenchymal Transition ◽

Adenocarcinoma Cells ◽

Signaling Axis ◽

Lung Adenocarcinoma Cells ◽

Paclitaxel Liposome

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 inpatients 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 activateRIPK1/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 viaCaspase-8 phosphorylation and lncCRLA expression, to which the dasatinib/paclitaxel liposome+siFLIP regimen was lethal.

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Emodin Inhibits ATP-Induced Proliferation and Migration by Suppressing P2Y Receptors in Human Lung Adenocarcinoma Cells

Cellular Physiology and Biochemistry ◽

10.1159/000485495 ◽

2017 ◽

Vol 44 (4) ◽

pp. 1337-1351 ◽

Cited By ~ 12

Author(s):

Xia Wang ◽

Long Li ◽

Ruijuan Guan ◽

Danian Zhu ◽

Nana Song ◽

...

Keyword(s):

Cell Proliferation ◽

Lung Adenocarcinoma ◽

Human Lung ◽

A549 Cells ◽

P2y Receptors ◽

Mesenchymal Transition ◽

Human Lung Adenocarcinoma ◽

Adenocarcinoma Cells ◽

Human Lung Adenocarcinoma Cells ◽

Lung Adenocarcinoma Cells

Background/Aims: Extracellular ATP performs multiple important functions via activation of P2 receptors on the cell surface. P2Y receptors play critical roles in ATP evoked response in human lung adenocarcinoma cells (A549 cells). Emodin is an anthraquinone derivative originally isolated from Chinese rhubarb, possesses anticancer properties. In this study we examined the inhibiting effects of emodin on proliferation, migration and epithelial-mesenchymal transition (EMT) by suppressing P2Y receptors-dependent Ca2+ increase and nuclear factor-κB (NF-KB) signaling in A549 cells. Methods: A549 cells were pretreated with emodin before stimulation with ATP for the indicated time. Then, intracellular Ca2+ concentration ([Ca2+]i) was measured by Fluo-8/AM staining. Cell proliferation and cell cycle progression were tested by CCK8 assay and flow cytometry In addition, wound healing and western blot were performed to determine cell migration and related protein levels (Bcl-2, Bax, claudin-1, NF-κB). Results: Emodin blunted ATP/UTP-induced increase of [Ca2+]i and cell proliferation concentration-dependently Meanwhile, it decreased ATP-induced cells accumulation in the S phase. Furthermore, emodin altered protein abundance of Bcl-2, Bax and claudin-1 and attenuated EMT caused by ATP. Such ATP-induced cellular reactions were also inhibited by a nonselective P2Y receptors antagonist, suramin, in a similar way to emodin. Besides, emodin could inhibit activation of NF-κB, thus suppressed ATP-induced proliferation, migration and EMT. Conclusion: Our results demonstrated that emodin inhibits ATP-induced proliferation, migration, EMT by suppressing P2Y receptors-mediated [Ca2+]i increase and NF-κB signaling in A549 cells.

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