scholarly journals Akt kinase LANCL2 functions as a key driver in EGFR-mutant lung adenocarcinoma tumorigenesis

2021 ◽  
Vol 12 (2) ◽  
Author(s):  
Yuqing Lou ◽  
Jianlin Xu ◽  
Yanwei Zhang ◽  
Wei Zhang ◽  
Xueyan Zhang ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Cell Line ◽  
Quantitative Polymerase Chain Reaction ◽  
Mutant Cell ◽  
A549 Cells ◽  
The Cancer Genome Atlas ◽  
Akt Kinase ◽  
Egfr Expression

AbstractEpidermal growth factor receptor (EGFR) is a key oncogene in lung adenocarcinoma (LUAD). Resistance to EGFR tyrosine kinase inhibitors is a major obstacle for EGFR-mutant LUAD patients. Our gene chip array, quantitative polymerase chain reaction validation, and shRNA-based high-content screening identified the Akt kinase lanthionine synthetase C-like protein 2 (LANCL2) as a pro-proliferative gene in the EGFR-mutant LUAD cell line PC9. Therefore, we investigated whether LANCL2 plays a role in promoting cell proliferation and drug resistance in EGFR-mutant LUAD. In silico clinical correlation analysis using the Cancer Genome Atlas Lung Adenocarcinoma dataset revealed a positive correlation between LANCL2 and EGFR expression and an inverse relationship between LANCL2 gain-of-function and survival in LUAD patients. The EGFR-mutant LUAD cell lines PC9 and HCC827 displayed higher LANCL2 expression than the non-EGFR-mutant cell line A549. In addition, LANCL2 was downregulated following gefitinib+pemetrexed combination therapy in PC9 cells. LANCL2 knockdown reduced proliferation and enhanced apoptosis in PC9, HCC827, and A549 cells in vitro and suppressed murine PC9 xenograft tumor growth in vivo. Notably, LANCL2 overexpression rescued these effects and promoted gefitinib + pemetrexed resistance in PC9 and HCC827 cells. Pathway analysis and co-immunoprecipitation followed by mass spectrometry of differentially-expressed genes in LANCL2 knockdown cells revealed enrichment of several cancer signaling pathways. In addition, Filamin A and glutathione S-transferase Mu 3 were identified as two novel protein interactors of LANCL2. In conclusion, LANCL2 promotes tumorigenic proliferation, suppresses apoptosis, and promotes gefitinib+pemetrexed resistance in EGFR-mutant LUAD cells. Based on the positive association between LANCL2, EGFR, and downstream Akt signaling, LANCL2 may be a promising new therapeutic target for EGFR-mutant LUAD.

scholarly journals Elevated Glutathione Peroxidase 2 Expression Promotes Cisplatin Resistance in Lung Adenocarcinoma

2020 ◽  
Vol 2020 ◽  
pp. 1-14
Author(s):  
He Du ◽  
Bi Chen ◽  
Nan-Lin Jiao ◽  
Yan-Hua Liu ◽  
San-Yuan Sun ◽  
...  
Keyword(s):  
Energy Metabolism ◽  
Glutathione Peroxidase ◽  
Lung Adenocarcinoma ◽  
Cell Line ◽  
A549 Cells ◽  
Disease Free Survival ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Normal Lung

The aim of this study was to explore the roles of GPX2, a member of the glutathione peroxidase family (GPXs, GSH-Px), in cisplatin (DDP) resistance in lung adenocarcinoma (LUAD). GPX2 was found to be the most significantly upregulated gene in a DDP-resistant A549/DDP cell line compared with the parental A549 cell line by RNA sequencing. The knockdown of GPX2 expression in A549/DDP cells inhibited cell proliferation in vitro and in vivo, decreased the IC50 values of DDP, induced apoptosis, inhibited the activities of GSH-Px and superoxide dismutase (SOD), inhibited ATP production and glucose uptake, and increased malondialdehyde (MDA) and reactive oxygen species (ROS) production; while GPX2 overexpression in A549 cells resulted in the opposite effects. Using gene set enrichment analysis (GSEA), we found that GPX2 may be involved in DDP resistance through mediating drug metabolism, the cell cycle, DNA repair and energy metabolism, and the regulation of an ATP-binding cassette (ABC) transporters member ABCB6, which is one of the hallmark genes in glycolysis. Moreover, immunohistochemistry revealed that GPX2 was upregulated in 58.6% (89/152) of LUAD cases, and elevated GPX2 expression was correlated with high expression of ABCB6, high 18-fluorodeoxyglucose (18F-FDG) uptake, and adverse disease-free survival (DFS) in our cohort. The Cancer Genome Atlas (TCGA) data also indicated that GPX2 expression was higher in LUAD than it was in normal lung tissues, and the mRNA expression levels of GPX2 and ABCB6 were positively correlated. In conclusion, our study demonstrates that GPX2 acts as oncogene in LUAD and promotes DDP resistance by regulating oxidative stress and energy metabolism.

scholarly journals Lipopolysaccharide administration alters extracellular vesicles in human lung-cancer cells and mice

2020 ◽  
Author(s):  
Leandra B. Jones ◽  
Sanjay Kumar ◽  
Courtnee’ R. Bell ◽  
Brennetta J. Crenshaw ◽  
Mamie T. Coats ◽  
...  
Keyword(s):  
Membrane Protein ◽  
Bacterial Infection ◽  
Cell Line ◽  
Extracellular Vesicles ◽  
A549 Cells ◽  
Human Lung Cancer ◽  
Diagnostic Tools ◽  
The Impact

AbstractExtracellular vesicles (EVs) play a fundamental role in cell and infection biology and have the potential to act as biomarkers for novel diagnostic tools. In this study, we explored the in vitro impact of bacterial lipopolysaccharide administration on a cell line that represents a target for bacterial infection in the host. Administration of lipopolysaccharide at varying concentrations to this A549 cell line caused only modest changes in cell death, but EV numbers were significantly changed. After treatment with the highest concentration of lipopolysaccharide, EVs derived from A549 cells packaged significantly less interleukin-6 and lysosomal-associated membrane protein 1. We also examined the impact of lipopolysaccharide administration on exosome biogenesis and cargo composition in BALB/c mice. Serum-isolated EVs from lipopolysaccharide-treated mice showed significantly increased lysosomal-associated membrane protein 1 and toll-like receptor 4 levels compared with EVs from control mice. In summary, this study demonstrated that EV numbers and cargo were altered using these in vitro and in vivo models of bacterial infection.

scholarly journals Inhibition of DKC1  Induces Telomere-related Senescence and Apoptosis in Lung Adenocarcinoma 

2020 ◽  
Author(s):  
Guangyan Kan ◽  
Ziyang Wang ◽  
Chunjie Sheng ◽  
Chen Yao ◽  
Yizhi Mao ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Cell Lines ◽  
Ectopic Expression ◽  
Telomerase Activity ◽  
Gene Expression Omnibus ◽  
Cell Senescence ◽  
The Cancer Genome Atlas ◽  
Poor Overall Survival

Abstract BackgroundLung cancer is one the most widely spread cancers in the world and half of the non-small cell lung cancers are lung adenocarcinoma (LUAD). Although there were several drugs been approved for LUAD therapy, a large portion of LUAD still can not be successfully treated due to lack of available therapeutic targets. Here, we investigated the oncogenic roles of DKC1 in LUAD and explored the potential mechanism and the possibility for LUAD therapy. MethodsWe analyzed Gene Expression Omnibus (GEO) and The Cancer Genome Atlas Program (TCGA) database and tissue microarray of LUAD. The expression of DKC1 and its correlation with prognosis were examined. In addition, Loss- and gain-of-function assays were used for oncogenic function of DKC1 both in vitro and in vivo.ResultsDKC1 is overexpressed in LUAD compared with normal tissues. High expression of DKC1 predicts the poor overall survival. Knockdown DKC1 in LUAD cell lines induced G1 phase arrest and inhibits cell proliferation. Ectopic expression of DKC1 could rescue the growth of LUAD cell lines. The abundance of DKC1 is positively correlated with TERC and TERT levels. DKC1 downregulation caused decreased TERC expression, reduced telomerase activity and shorten telomere, and thus eventually led to cell senescence and apoptosis.ConclusionsOur results show that high DKC1 expression indicates poor prognosis and DKC1 downregulation could induce telomere-related cell senescence and apoptosis. This study suggests that DKC1 could serve as a candidate diagnostic biomarker and therapeutic target for LUAD.

scholarly journals BIOM-22. EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR) AS A MOLECULAR DETERMINANT OF GLIOBLASTOMA RESPONSE TO DOPAMINE RECEPTOR 2 (DRD2) INHIBITORS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii6-ii6
Author(s):  
Yuyu He ◽  
Jie Li ◽  
Tomoyuki Koga ◽  
Jun Ma ◽  
Sanjay Dhawan ◽  
...  
Keyword(s):  
Dopamine Receptor ◽  
Ectopic Expression ◽  
Growth Factor Receptor ◽  
Inverse Correlation ◽  
Primary Brain Tumor ◽  
The Cancer Genome Atlas ◽  
Dopamine Synthesis ◽  
Egfr Expression

Abstract BACKGROUND There are ongoing clinical trials exploring the efficacy of dopamine receptor 2 (DRD2) inhibition against glioblastomas, the most common primary brain tumor. Here we examine potential molecular determinants of this efficacy. METHODS The Cancer Genome Atlas (TCGA) glioblastoma database and other published mRNA profiles were used to analyze the DRD2 and EGFR expression pattern. In vitro and in vivo responses to DRD2 inhibitors were determined using patient derived xenograft (PDX) glioblastoma models. Immunohistochemical studies were performed on clinically annotated glioblastoma samples derived from patients treated with ONC201, a DRD2 inhibitor. RESULTS Analysis of clinical glioblastoma specimens derived from independent patient cohorts revealed an inverse correlation between EGFR and DRD mRNA expression, with implication that signaling mediated by these proteins shares overlapping functions. In independent panels of PDX glioblastoma lines, high EGFR expression was associated with poor in vitro and in vivo response to DRD2 inhibitors, including haloperidol and ONC201. Moreover, ectopic expression of a constitutively active EGFR, EGFRvIII, suppressed glioblastoma sensitivity to ONC201. DRD2 expression positively correlated with expression of rate-limiting enzymes for dopamine synthesis as well as dopamine secretion, suggesting contribution of autocrine DRD2 signaling. Analysis of specimens from patients treated with ONC201 (n = 15) showed an inverse correlation between the intensity of EGFR staining and clinical response. The median overall survival for patients with high and low EGFR staining was 162 and 373 days, respectively (p = 0.037). CONCLUSIONS High EGFR expression is a determinant of poor glioblastoma response to DRD2. This finding should inform future clinical trial designs.

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