scholarly journals UBE2T promotes autophagy via the p53/AMPK/mTOR signaling pathway in lung adenocarcinoma

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Jinhong Zhu ◽  
Haijiao Ao ◽  
Mingdong Liu ◽  
Kui Cao ◽  
Jianqun Ma
Keyword(s):  
Lung Cancer ◽  
Overall Survival ◽  
Lung Adenocarcinoma ◽  
Cancer Cells ◽  
Signaling Pathway ◽  
Risk Score ◽  
A549 Cells ◽  
Mtor Signaling ◽  
Lung Cancer Cells ◽  
Mtor Signaling Pathway

Abstract Background Ubiquitin-conjugating enzyme E2T (UBE2T) acts as an oncogene in various types of cancer. However, the mechanisms behind its oncogenic role remain unclear in lung cancer. This study aims to explore the function and clinical relevance of UBE2T in lung cancer. Methods Lentiviral vectors were used to mediate UBE2T depletion or overexpress UBE2T in lung cancer cells. CCK8 analysis and western blotting were performed to investigate the effects of UBE2T on proliferation, autophagy, and relevant signaling pathways. To exploit the clinical significance of UBE2T, we performed immunohistochemistry staining with an anti-UBE2T antibody on 131 NSCLC samples. Moreover, we downloaded the human lung adenocarcinoma (LUAD) dataset from The Cancer Atlas Project (TCGA). Lasso Cox regression model was adopted to establish a prognostic model with UBE2T-correlated autophagy genes. Results We found that UBE2T stimulated proliferation and autophagy, and silencing this gene abolished autophagy in lung cancer cells. As suggested by Gene set enrichment analysis, we observed that UBE2T downregulated p53 levels in A549 cells and vice versa. Blockade of p53 counteracted the inhibitory effects of UBE2T depletion on autophagy. Meanwhile, the AMPK/mTOR signaling pathway was activated during UBE2T-mediated autophagy, suggesting that UBE2T promotes autophagy via the p53/AMPK/mTOR pathway. Interestingly, UBE2T overexpression increased cisplatin-trigged autophagy and led to cisplatin resistance of A549 cells, whereas inhibiting autophagy reversed drug resistance. However, no association was observed between UEB2T and overall survival in a population of 131 resectable NSCLC patients. Therefore, we developed and validated a multiple gene signature by considering UBE2T and its relevance in autophagy in lung cancer. The risk score derived from the prognostic signature significantly stratified LUAD patients into low- and high-risk groups with different overall survival. The risk score might independently predict prognosis. Interestingly, nomogram and decision curve analysis demonstrated that the signature’s prognostic accuracy culminated while combined with clinical features. Finally, the risk score showed great potential in predicting clinical chemosensitivity. Conclusions We found that UBE2T upregulates autophagy in NSCLC cells by activating the p53/AMPK/mTOR signaling pathway. The clinical predicting ability of UBE2T in LUAD can be improved by considering the autophagy-regulatory role of UBE2T.

scholarly journals CircHIPK3/miR-381-3p axis modulates proliferation, migration, and glycolysis of lung cancer cells by regulating the AKT/mTOR signaling pathway

2020 ◽  
Vol 15 (1) ◽  
pp. 683-695
Author(s):  
Feng Gu ◽  
Junhan Zhang ◽  
Lin Yan ◽  
Dong Li
Keyword(s):  
Lung Cancer ◽  
Cancer Cells ◽  
Signaling Pathway ◽  
Cancer Progression ◽  
Mtor Signaling ◽  
Lung Cancer Cells ◽  
Luciferase Reporter ◽  
Mtor Signaling Pathway

AbstractLung cancer is a lethal malignancy. Plenty of circular RNAs (circRNAs) have been identified to be the vital regulators in lung cancer development. Here, we intended to clarify the functional role of circRNA HIPK3 (circHIPK3, also called hsa_circ_0021593) and its underlying mechanism of action. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was employed to evaluate the levels of circHIPK3 and miR-381-3p. Cell viability and apoptosis rate were monitored by Cell Counting Kit-8 assay and flow cytometry, respectively. Cell migration was estimated through the Transwell assay. To assess glycolysis, commercial kits were utilized to measure the levels of glucose and lactate and the enzyme activity of hexokinase-2 (HK2). Expression of related proteins was detected via western blot analysis. The target connection between circHIPK3 and miR-381-3p was validated by dual-luciferase reporter, RIP, and pull-down assays. The role of circHIPK3 in vivo was determined via the xenograft assay. CircHIPK3 was upregulated, while miR-381-3p was downregulated in lung cancer tissues and cells. And circHIPK3 deficiency inhibited lung cancer progression by lowering cell proliferation, migration, glycolysis, and promoting apoptosis of lung cancer cells in vitro. MiR-381-3p was a target of circHIPK3, and miR-381-3p interference alleviated circHIPK3 knockdown-induced lung cancer progression inhibition. CircHIPK3 could activate the protein kinase B/mammalian target of rapamycin (AKT/mTOR) signaling pathway. Moreover, circHIPK3 knockdown suppressed tumor growth in vivo by inactivating the AKT/mTOR signaling pathway. In conclusion, the silencing of circHIPK3 inhibited lung cancer progression, at least in part, by sponging miR-381-3p and inactivating the AKT/mTOR signaling pathway.

Prucalopride inhibits lung cancer cell proliferation, invasion, and migration through blocking of the PI3K/AKT/mTor signaling pathway

2019 ◽  
Vol 39 (2) ◽  
pp. 173-181 ◽  
Author(s):  
M Chen ◽  
L-L Zhu ◽  
J-L Su ◽  
G-L Li ◽  
J Wang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Cells ◽  
Signaling Pathway ◽  
Human Lung ◽  
Mtor Signaling ◽  
Lung Cancer Cells ◽  
Human Lung Cancer ◽  
Mtor Signaling Pathway ◽  
Invasion And Migration ◽  
And Migration

Lung cancer is the main cause of cancer incidence and mortality around the world. Prucalopride is an agonist for the 5-hydroxytryptamine 4 receptor, but it was unknown whether prucalopride could be used to treat lung cancer. To investigate the biological effects of prucalopride on proliferation, apoptosis, invasion, and migration of lung cancer cells, and its underlying molecular mechanism in the progression of lung cancer, we performed this study. The Cell Counting Kit 8 assay was used to measure the proliferation of A549/A427 lung cancer cells treated with prucalopride. Transwell assay was applied to evaluate cell invasion and migration. Cell apoptosis was detected by flow cytometry and Western blot analyses. The expression levels of related proteins in the PI3K/AKT/mTor signaling pathway were analyzed by Western blotting. Prucalopride inhibited the proliferation, invasion, and migration of A549/A427 human lung cancer cells. It also induced autophagy and apoptosis and decreased the expression of the phosphorylated protein kinase B (AKT) and mammalian target of rapamycin (mTor) in these cells. This study implied an inhibitory role for prucalopride in the progression of human lung cancer.

scholarly journals Knockdown of RAD54B expression reduces cell proliferation and induces apoptosis in lung cancer cells

2019 ◽  
Vol 47 (11) ◽  
pp. 5650-5659 ◽  
Author(s):  
Chuan Xu ◽  
Di Liu ◽  
Hong Mei ◽  
Jian Hu ◽  
Meng Luo
Keyword(s):  
Lung Cancer ◽  
Cell Proliferation ◽  
Protein Expression ◽  
Lung Adenocarcinoma ◽  
Cancer Cells ◽  
Caspase 3 ◽  
A549 Cells ◽  
Lung Cancer Cells ◽  
Gene And Protein Expression ◽  
Healthy Lung

Objective RAD54 homolog B (RAD54B), a member of the SNF2/SWI2 superfamily, is implicated in homologous recombination, and high RAD54B expression predicts the prognostic outcomes of lung adenocarcinoma. However, its role in lung carcinogenesis was unclear so this was determined in the present study. Methods We evaluated the gene and protein expression of RAD54B in 15 lung adenocarcinoma tissues and matched adjacent healthy lung tissues by real-time PCR, immunohistochemical staining, and western blotting. A549 lung cancer cells were transduced with lentivirus carrying small hairpin RNA (shRNA) against RAD54B (shRAD54B) or control shRNA (shCtrl), and cell proliferation, viability, apoptosis, and caspase 3/7 activity were evaluated. Results RAD54B protein expression was significantly higher in lung adenocarcinoma tissues than in healthy lung tissues. RAD54B gene expression was high in A549 cells but was efficiently knocked down using shRAD54B with an infection efficiency of 80% and a knockdown ratio of 72.2% compared with shCtrl. Suppressing RAD54B expression in A549 cells significantly reduced cell proliferation and caspase 3/7 activity, and significantly increased the apoptotic rate. Conclusions RAD54B exerts an oncogenic role in lung cancer cell proliferation.

scholarly journals Nurr1 promotes lung cancer apoptosis via enhancing mitochondrial stress and p53-Drp1 pathway

2019 ◽  
Vol 14 (1) ◽  
pp. 262-274
Author(s):  
Shu Zhao ◽  
Peng Li ◽  
Peng Wang ◽  
Jing Yang ◽  
Peng Song ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Mitochondrial Dysfunction ◽  
Cancer Cells ◽  
Signaling Pathway ◽  
A549 Cells ◽  
Lung Cancer Cells ◽  
Lung Cancer Death ◽  
Mitochondrial Stress ◽  
Mitochondrial Homeostasis ◽  
A549 Lung

AbstractObjectiveMitochondrial homeostasis is vital for the progression of lung cancer. Nurr1 has been identified as a novel mediator of mitochondrial homeostasis in several types of cancers. The aim of our study was to investigate whether Nurr1 modulates the viability of A549 lung cancer cells by inducing mitochondrial dysfunction, with a focus on the p53-Drp1 signaling pathway.Methodswestern blotting, ELISA and immunofluorescence assay was used to verify the alterations of cell death. siRNA was used to determine the role of p53-Drp1 pathway in lung cancer death.ResultsNurr1 was downregulated in A549 lung cancer cells compared to normal pulmonary epithelial cells. Interestingly, overexpression of Nurr1 reduced the viability of A549 lung cancer cells by activating apoptosis and mitochondrial stress. At the molecular level, we provide data to support the regulatory effects of Nurr1 on the p53-Drp1 signaling pathway. Blockade of the p53-Drp1 signaling pathway abolished the proapoptotic action of Nurr1 on A549 cells and sustained mitochondrial homeostasis.ConclusionTaken together, our results depict the tumor-suppressive role played by Nurr1 in A549 lung cancer in vitro and show that the anticancer effects of Nurr1 are executed via triggering of mitochondrial dysfunction and activation of the p53-Drp1 signaling pathway.

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