scholarly journals MK2 Expression Promotes Non-Small Cell Lung Cancer Cell Death and Predicts Survival

2021 ◽  
Author(s):  
Othello Del Rosario ◽  
Karthik Suresh ◽  
Medha Kallem ◽  
Gayatri Singh ◽  
Anika Shah ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Death ◽  
Small Cell Lung Cancer ◽  
Cell Lines ◽  
Caspase 3 ◽  
Nuclear Translocation ◽  
Carcinoma Cell ◽  
Small Cell ◽  
Small Cell Lung ◽  
Carcinoma Cell Lines

Non-small cell lung cancers demonstrate intrinsic resistance to cell death even in response to chemotherapy. Previous work suggested that defective nuclear translocation of active caspase 3 may play a role in resistance to cell death. Separately, our group has identified that mitogen activated protein kinase activated protein kinase 2 (MK2) is required for nuclear translocation of active caspase 3 in the execution of apoptosis. This study demonstrates a relatively low expression of MK2 in non-small cell lung carcinoma cell lines compared to small cell carcinoma cell lines. Further, overexpression of MK2 in non-small cell lung carcinoma cell lines results in increased caspase 3 activity and caspase 3 mediated cell death. Higher MK2 transcript levels were observed in patients with earlier-stage non-small cell lung cancer. Higher expression of MK2 is associated with better survival in patients with early stage non-small cell lung cancer across two independent clinical datasets. Using data sets spanning multiple cancer types, we observed improved survival with higher MK2 expression was unique to lung adenocarcinoma. Mechanistically, MK2 promotes nuclear translocation of caspase 3 leading to PARP1 cleavage and execution of cell death. While MK2 can directly phosphorylate caspase 3, neither phosphorylation status of caspase 3 nor the kinase activity of MK2 impacts caspase 3 activation, nuclear translocation and execution of cell death. Rather, a non-kinase function of MK2, specifically trafficking via its nuclear localization sequence, is required for caspase 3 mediated cell death. In summary this study highlights the importance of a non-enzymatic function of MK2 in the execution of apoptosis, which may be leveraged in the adjunctive treatment of NSCLC or other conditions where regulation of apoptosis is crucial.

scholarly journals Clozapine Induces Autophagic Cell Death in Non-Small Cell Lung Cancer Cells

2015 ◽  
Vol 35 (3) ◽  
pp. 945-956 ◽  
Author(s):  
Yu-Chun Yin ◽  
Chao-Cheng Lin ◽  
Tzu-Ting Chen ◽  
Jen-Yeu Chen ◽  
Hui-Ju Tsai ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Cycle ◽  
Cell Lines ◽  
Carcinoma Cell ◽  
Small Cell Lung Carcinoma ◽  
Small Cell ◽  
Bafilomycin A1 ◽  
Small Cell Lung ◽  
Cell Lung Carcinoma ◽  
Carcinoma Cell Lines

Background/Aims: Previous studies have shown that patients with schizophrenia have a lower incidence of cancer than the general population, and several antipsychotics have been demonstrated to have cytotoxic effects on cancer cells. However, the mechanisms underlying these results remain unclear. The present study aimed to investigate the effect of clozapine, which is often used to treat patients with refractory schizophrenia, on the growth of non-small cell lung carcinoma cell lines and to examine whether autophagy contributes to its effects. Methods: A549 and H1299 cells were treated with clozapine, and cell cytotoxicity, cell cycle and autophagy were then assessed. The autophagy inhibitor bafilomycin A1 and siRNA-targeted Atg7 were used to determine the role of autophagy in the effect of clozapine. Results: Clozapine inhibited A549 and H1299 proliferation and increased p21 and p27 expression levels, leading to cell cycle arrest. Clozapine also induced a high level of autophagy, but not apoptosis, in both cell lines, and the growth inhibitory effect of clozapine was blunted by treatment with the autophagy inhibitor bafilomycin A1 or with an siRNA targeting atg7. Conclusions: Clozapine inhibits cell proliferation by inducing autophagic cell death in two non-small cell lung carcinoma cell lines. These findings may provide insights into the relationship between clozapine use and the lower incidence of lung cancer among patients with schizophrenia.

scholarly journals Paclitaxel-induced apoptosis in non–small cell lung cancer cell lines is associated with increased caspase-3 activity

2000 ◽  
Vol 119 (4) ◽  
pp. 795-803 ◽  
Author(s):  
Tracey L. Weigel ◽  
Michael T. Lotze ◽  
Peter K. Kim ◽  
Andrew A. Amoscato ◽  
James D. Luketich ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cell Lung Cancer ◽  
Caspase 3 ◽  
Small Cell ◽  
Lung Cancer Cell ◽  
Small Cell Lung ◽  
Induced Apoptosis

scholarly journals Clinically Relevant Chemotherapeutics Have the Ability to Induce Immunogenic Cell Death in Non-Small Cell Lung Cancer

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1474 ◽  
Author(s):  
Tal Flieswasser ◽  
Jinthe Van Loenhout ◽  
Laurie Freire Boullosa ◽  
Astrid Van den Eynde ◽  
Jorrit De Waele ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Death ◽  
Small Cell Lung Cancer ◽  
Cell Lines ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Immunogenic Cell Death ◽  
Small Cell Lung

The concept of immunogenic cell death (ICD) has emerged as a cornerstone of therapy-induced anti-tumor immunity. To this end, the following chemotherapies were evaluated for their ability to induce ICD in non-small cell lung cancer (NSCLC) cell lines: docetaxel, carboplatin, cisplatin, oxaliplatin and mafosfamide. The ICD hallmarks ATP, ecto-calreticulin, HMGB1, phagocytosis and maturation status of dendritic cells (DCs) were assessed in vitro. Furthermore, an in vivo vaccination assay on C57BL/6J mice was performed to validate our in vitro results. Docetaxel and the combination of docetaxel with carboplatin or cisplatin demonstrated the highest levels of ATP, ecto-calreticulin and HMGB1 in three out of four NSCLC cell lines. In addition, these regimens resulted in phagocytosis of treated NSCLC cells and maturation of DCs. Along similar lines, all mice vaccinated with NSCLC cells treated with docetaxel and cisplatin remained tumor-free after challenge. However, this was not the case for docetaxel, despite its induction of the ICD-related molecules in vitro, as it failed to reject tumor growth at the challenge site in 60% of the mice. Moreover, our in vitro and in vivo data show the inability of oxaliplatin to induce ICD in NSCLC cells. Overall with this study we demonstrate that clinically relevant chemotherapeutic regimens in NSCLC patients have the ability to induce ICD.

scholarly journals A novel PPARɣ ligand, PPZ023, overcomes radioresistance via ER stress and cell death in human non-small-cell lung cancer cells

2020 ◽  
Vol 52 (10) ◽  
pp. 1730-1743
Author(s):  
Tae Woo Kim ◽  
Da-Won Hong ◽  
Chang-Mo Kang ◽  
Sung Hee Hong
Keyword(s):  
Lung Cancer ◽  
Cell Death ◽  
Er Stress ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Caspase 3 ◽  
Small Cell ◽  
Small Cell Lung ◽  
Cytochrome C Release ◽  
Anticancer Effects

Abstract Peroxisome proliferator-activated receptor gamma (PPARɣ) agonists exert powerful anticancer effects by suppressing tumor growth. In this study, we developed PPZ023 (1-(2-(ethylthio)benzyl)-4-(2-methoxyphenyl)piperazine), a novel PPAR ligand candidate, and investigated the underlying signaling pathways in both non-small-cell lung cancer (NSCLC) and radio-resistant NSCLC cells. To identify whether PPZ023 has anticancer effects in NSCLC and radioresistant NSCLC cells, we performed WST-1, LDH, Western blot, and caspase-3 and -9 activity assays. Furthermore, we isolated exosomes from PPZ023-treated NSCLC cells and studied cell death signaling. PPZ023 reduces cell viability and increases LDH cytotoxicity and caspase-3 activity in NSCLC cells. PPZ023 induces cell death by generating reactive oxygen species (ROS) and triggering mitochondrial cytochrome c release. PPZ023 treatment causes cell death via the PERK–eIF2α–CHOP axis in both NSCLC cell lysates and exosomes, and PERK and CHOP knockdown significantly blocks ER stress-mediated apoptosis by reducing cleaved caspase-3. Interestingly, diphenyleneiodonium (DPI, a Nox inhibitor) inhibits PPZ023-induced cell death via ER stress, and PPARɣ knockdown inhibits PPZ023-induced ROS, ER stress, and cell death. Moreover, PPZ023, in combination with radiation, causes synergic cell death via exosomal ER stress in radioresistant NSCLC cells, indicating that PPZ023/radiation overcomes radioresistance. Taken together, our results suggest that PPZ023 is a powerful anticancer reagent for overcoming radioresistance.

The Key microRNAs Regulated the Development of Non-small Cell Lung Cancer by Targeting TGF-β-induced epithelial–mesenchymal Transition

2019 ◽  
Vol 22 (4) ◽  
pp. 238-244 ◽  
Author(s):  
Gang Chen ◽  
Bo Ye
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lines ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Nsclc Cell ◽  
Normal Lung ◽  
Migration And Invasion ◽  
Small Cell Lung ◽  
Mesenchymal Transition

Purpose: Epithelial-to-Mesenchymal Transition (EMT) was reported to play a key role in the development of Non-Small Cell Lung Cancer (NSCLC). The process of EMT is regulated by the changes of miRNAs expression. However, it is still unknown which miRNA changed the most in the process of canceration and whether these changes played a role in tumor development. Methods: A total of 36 SCLC patients treated in our hospital between 11th, 2015 and 10th, 2017 were enrolled. The samples of cancer tissues and paracancer tissues of patients were collected and analyzed. Then, the miRNAs in normal lung cells and NSCLC cells were also analyzed. In the presence of TGF-β, we transfected the miRNA mimics or inhibitor into NSCLC cells to investigate the role of the significantly altered miRNAs in cell migration and invasion and in the process of EMT. Results: MiR-330-3p was significantly up-regulated in NSCLC cell lines and tissues and miRNA- 205 was significantly down-regulated in NSCLC cell lines and NSCLC tissues. Transfected miRNA-205 mimics or miRMA-330-3p inhibitor inhibited the migration and invasion of NCIH1975 cell and restrained TGF-β-induced EMT in NSCLC cells. Conclusion: miRNA-330-3p and miRNA-205 changed the most in the process of canceration in NSCLC. Furthermore, miR-330-3p promoted cell invasion and metastasis in NSCLC probably by promoting EMT and miR-205 could restrain NSCLC likely by suppressing EMT.

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