scholarly journals USP46 inhibits cell proliferation in lung cancer through PHLPP1/AKT pathway

2020 ◽  
Author(s):  
Wei Wang ◽  
Meng Chen ◽  
Hailing Xu ◽  
Dongqing Lv ◽  
Suna Zhou ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Proliferation ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Lung Cancer Cells ◽  
Akt Pathway ◽  
Cancer Cell Proliferation ◽  
Lung Cancer Cell ◽  
Knock Down

Abstract Background: USP46 has been shown to function as tumor suppressor in colon cancer and renal cell carcinoma. However, its specific role in other cancers remains unknown. This study was aimed to investigate the role of USP46 in lung cancer tumorigenesis, and to identify the underlying mechanism. Methods: Quantitative Real Time-Polymerase Chain Reaction (qRT-PCR) and Western Blotting (WB) were used to measure the expression levels of USP46 and PHLPP1 in lung cancer tissue and adjacent normal tissue from lung cancer patients. The functional role of USP46 in regulating proliferation in lung cancer cells were examined by cell proliferation assay, radiation assay, genetic overexpression and knock down and chemical inhibition of relevant genes. The underlying mechanisms were investigated in multiple lung cancer cell line models by co-immunoprecipitation and ubiquitination assays. Results: This study identified strong downregulation of USP46 and PHLPP1 expression in lung cancer tissues relative to normal adjacent tissues. USP46 was further shown to inhibit lung cancer cell proliferation under normal growth conditions and during radiation induced DNA damage by antagonizing the ubiquitination of PHLPP1 resulting in the inhibition of AKT signaling. The effect of USP46 knock down on lung cancer cell proliferation was significantly reversed by exposure to radiation and AKT inhibition. Conclusions: USP46 is down-regulated in lung cancer, and it suppresses proliferation of lung cancer cells by inhibiting PHLPP1/AKT pathway. AKT inhibition slows proliferation of USP46 down-regulated lung cancer cells exposed to radiation suggesting a potential therapeutic avenue for USP46 down-regulated lung cancer through a combination of radiation and AKT inhibitor treatment.

scholarly journals USP46 Inhibits Cell Proliferation in Lung Cancer through PHLPP1/AKT Pathway

2020 ◽  
Vol 2020 ◽  
pp. 1-10
Author(s):  
Wei Wang ◽  
Meng Chen ◽  
Hailing Xu ◽  
Dongqing Lv ◽  
Suna Zhou ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Proliferation ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Lung Cancer Cells ◽  
Akt Pathway ◽  
Cancer Tissue ◽  
Cancer Cell Proliferation ◽  
Lung Cancer Cell ◽  
Underlying Mechanisms

Previous studies have shown that ubiquitin-specific protease 46 (USP46) is a tumor suppressor in colon cancer and renal cell carcinoma. However, its specific role in other cancers is still poorly understood. This study is aimed at investigating the role of USP46 in lung cancer tumorigenesis and identifying its underlying mechanisms. Quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting (WB) were used to measure the expression levels of USP46 and PHLPP1 in lung cancer tissue and adjacent normal tissue from patients with lung cancer. We examined the ability of USP46 to regulate cell proliferation in lung cancer cells via cell proliferation assay, radiation assay, genetic overexpression and knockdown, and chemical inhibition of relevant genes. We investigated the underlying mechanisms in multiple lung cancer cell line models by coimmunoprecipitation and ubiquitination assays. In this study, we identified a strong downregulation of the expressions of USP46 and PHLPP1 in lung cancer tissues relative to normal adjacent tissues. USP46 was further shown to inhibit lung cancer cell proliferation under conditions of normal growth and during radiation-induced DNA damage by antagonizing the ubiquitination of PHLPP1 resulting in the inhibition of AKT signaling. Exposure to radiation and AKT inhibition significantly reversed the effect of USP46 siRNA on lung cancer cell proliferation. USP46 is downregulated in lung cancer and suppresses the proliferation of lung cancer cells by inhibiting the PHLPP1/AKT pathway. AKT inhibition slows the proliferation of lung cancer cells that have been downregulated by USP46 and exposed to radiation. This suggests a potential therapeutic avenue for USP46-downregulated lung cancer through a combination of radiation and AKT inhibitor treatment.

Ras association domain family 1C protein stimulates human lung cancer cell proliferation

2006 ◽  
Vol 291 (6) ◽  
pp. L1185-L1190 ◽  
Author(s):  
Yousef G. Amaar ◽  
Marlon G. Minera ◽  
Laurice K. Hatran ◽  
Donna D. Strong ◽  
Subburaman Mohan ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Proliferation ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Small Interfering Rna ◽  
Lung Cancer Cells ◽  
Cancer Cell Proliferation ◽  
Lung Cancer Cell ◽  
Domain Family ◽  
Interfering Rna

Recently, the Ras association domain family 1 gene ( RASSF1) has been identified as a Ras effector encoding two major mRNA forms, RASSF1A and RASSF1C, derived by alternative promoter selection and alternative mRNA splicing. RASSF1A is a tumor suppressor gene. However, the function of RASSF1C, both in normal and cancer cells, is still unknown. To learn more about the function of RASSF1C in human cancer cells, we tested the effect of silencing RASSF1C mRNA with small interfering RNA on lung cancer cells (NCI H1299) that express RASSF1C but not RASSF1A. Small interfering RNA specific for RASSF1C reduced RASSF1C mRNA levels compared with controls. This reduction in RASSF1C expression caused a significant decrease in lung cancer cell proliferation. Furthermore, overexpression of RASSF1C increased cell proliferation in lung cancer cells. Finally, we found that RASSF1C, unlike RASSF1A, does not upregulate N-cadherin 2 and transglutaminase 2 protein expression in NCI H1299 lung cancer cells. This suggests that RASSF1C and RASSF1A have different effector targets. Together, our findings suggest that RASSF1C, unlike RASSF1A, is not a tumor suppressor but rather stimulates lung cancer cell proliferation.

Effect of GPR87 on cell proliferation via KRAS signaling pathway in p53-mutant lung cancer cells.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14713-e14713
Author(s):  
Takayuki Nakano ◽  
Nariyasu Nakashima ◽  
Dage Liu ◽  
Xia Zhang ◽  
Natsumi Matsuura ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Proliferation ◽  
Cell Viability ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Human Tumor ◽  
Signal Pathway ◽  
Lung Cancer Cells ◽  
Lung Cancer Cell ◽  
P53 Expression

e14713 Background: GPR87 is a member of the cell surface molecular G protein-coupled receptors (GPCRs) family and suggested to contribute to the viability of human tumor cells including lung cancer cell. The mechanism of GPR87 in promote cell proliferation is still not yet well understand. p53 was reported to take an important role in keeping cell viability of GPR87-expressing cells. However, most of lung cancer cells possess p53 mutation. In the present study, several reported signal pathway were investigated in lung cancer cells. Methods: Two p53 mutant GPR87-overexpressing lung cancer cell H358 and PC9 lung cancer cell was investigated. An adenoviral vector that encoded a short hairpin siRNA targeting the GPR87 gene (Ad-shGPR87) was constructed. Real-time RT-PCR was performed to evaluate gene expressions and westen blotting analysis for protein expression. MTT assay was used to evaluate the cell viability. Results: Ad-shGPR87 effectively inhibited the GPR87 expression and significantly reduced the percentage of viable cells in GPR87-overexpression H358 and PC9 cell. Regading the signal pathway, there was no p53 expression in H358 cell and no changes in PC9 cell. However, both cells showed a significant decrease in KRAS and c-Myc gene expression 5 days after Ad-shGPR87 transfection. On the other hand, after Ad-shGPR87 transfection, Akt and Cyclin-D1gene expression decrease slightly in H358, but not in the PC9 cell. Conclusions: Theses result show that GPR87 may promoting cell proliferation through several signaling pathways and that the active in p53 mutant cell may linked to KRAS pathway in lung cancer cell.

MicroRNA-5100 Modulates Lung Cancer Cell Proliferation and Apoptosis via Inhibiting X-Linked Inhibitor of Apoptosis Protein (XIAP) Expression

2021 ◽  
Vol 11 (10) ◽  
pp. 2037-2043
Author(s):  
Dongshen Ding ◽  
Liang Hong ◽  
Chang Shu
Keyword(s):  
Lung Cancer ◽  
Cell Proliferation ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Luciferase Assay ◽  
Cancer Cell Proliferation ◽  
Lung Cancer Cell ◽  
Dual Luciferase Assay ◽  
Xiap Expression

This study assesses the miR-5100 expression and its function in human lung cancer. The expression of miR-5100 was analyzed by miScript miRNA method. Cancer cells were transfected with miR-5100 mimics (miR-5100), miR-5100 inhibitors (ASO-miR-5100), XIAP inhibitors (si-XIAP), negative controls (NC) followed by analysis of cell proliferation by MTT and apoptosis by flow cytometry, the expression of XIAP related proteins by Western blot. miR-5100’ target was predicted by bioinformatics website and verified by dual luciferase assay. Finally, a xenogeneic tumor inhibition model was established to detect tumor progression after treatments. Lung cancer cells and tissues exhibited significantly reduced miR-5100 level. Dual luciferase assay showed that miR-5100 bound XIAP 3′-UTR and reduced XIAP mRNA and protein level. Further, miR-5100 inhibited cell proliferation, increased apoptosis and the expression of cleaved-capsase-3 and cleaved-capsase-9, the XIAP downstream factor. Finally, miR-5100 inhibited tumor growth, decreased cellular proliferation and promoted apoptosis, accompanied by reduced XIAP expression in vivo. miR-5100 inhibits lung cancer cell proliferation and enhances apoptosis through inhibiting XIAP expression in vitro and in vivo.

scholarly journals Anticancer Effects of Auranofin in Human Lung Cancer Cells Through Increasing Intracellular ROS Levels and GSH Depletion

2021 ◽  
Author(s):  
Sun Hyang Park ◽  
Xia Ying Cui ◽  
Woo Hyun Park
Keyword(s):  
Lung Cancer ◽  
Cell Proliferation ◽  
Cell Death ◽  
Cancer Cells ◽  
Cancer Cell ◽  
A549 Cells ◽  
Thioredoxin Reductase ◽  
Lung Cancer Cells ◽  
Blue Staining ◽  
Lung Cancer Cell

Abstract Purpose Auranofin is known to inhibit thioredoxin reductase (TrxR) and has promising anticancer activity in several cancer types. However, at present, there is no clear explanation for the mechanism underlying the inhibitory effects of Auranofin on lung cancer cell growth. In this study, we evaluated the antigrowth effects of Auranofin in cells from various lung cancer cell lines with regard to cell death, reactive oxygen species (ROS), and glutathione (GSH) levels.Methods Cell proliferation was assessed using the trypan blue staining cell counting. ROS levels including O2·-, GSH levels, and MMP (∆Ψm) loss were measured using a flow cytometry. Apoptosis was determined with annexin V-PI staining assay and the change of apoptosis-related protein level was detected by western blotting. TrxR activity was evaluated using a thioredoxin reductase colorimetric assay kit.Results Treatment with Auranofin inhibited cell proliferation and induced cell death based on cell number at 24 h in Calu-6, A549, SK-LU-1, NCI-H460, and NCI-H1299 cells. In addition, Auranofin led to increased ROS levels including O2·- and GSH depletion in these cells. Treatment with N-acetyl cysteine (NAC) attenuated the growth inhibition, mitochondrial membrane potential (MMP, ∆Ψm) loss, and increased ROS levels and GSH depletion in Auranofin-treated Calu-6 and A549 cells. By contrast, L-buthionine sulfoximine (BSO) enhanced cell death, MMP (∆Ψm) loss, ROS production, and GSH depletion. Furthermore, the western blot analysis indicated that Auranofin-induced caspase-3 activation and poly (ADP ribose) polymerase (PARP) cleavage, both of which were prevented by pretreatment with NAC but enhanced by pretreatment with BSO in Calu-6 and A549 cells. Consistent with these changes, the decrease in TrxR activity caused by Auranofin was enhanced by preincubation with BSO and restored in response to the preincubation with NAC in both Calu-6 and A549 cells.Conclusion Our present findings demonstrate that Auranofin-induced cell death is tightly related to oxidative stress in lung cancer cells.

Exosomal lncRNA FOXD3-AS1 upregulates ELAVL1 expression and activates PI3K/Akt pathway to enhance lung cancer cell proliferation, invasion, and 5-fluorouracil resistance

2021 ◽  
Author(s):  
Guangxian Mao ◽  
Zhimin Mu ◽  
Da Wu
Keyword(s):  
Lung Cancer ◽  
Cell Proliferation ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Cancer Progression ◽  
Rna Binding ◽  
Rna Binding Protein ◽  
A549 Cells ◽  
Akt Pathway ◽  
Lung Cancer Cell

Abstract Long non-coding RNA (lncRNA) FOXD3-AS1 expression is upregulated in lung cancer; however, its effect and mechanism on 5-fluorouracil (5-FU) resistance remain unclear. In this study, we determined the effects of FOXD3-AS1-enriched exosomes derived from lung cancer cells on the proliferation, invasion, and 5-FU resistance of lung cancer cells. Online bioinformatics database analysis showed that FOXD3-AS1 was upregulated in lung cancer progression. Real-time quantitative PCR results confirmed that FOXD3-AS1 expression was upregulated in lung cancer tissues and cell lines, and FOXD3-AS1 was greatly enriched in lung cancer cell-derived exosomes. ELAV-like RNA-binding protein 1 (ELAVL1) was identified as an RNA-binding protein of FOXD3-AS1. The lung cancer cell-derived exosomes promoted A549 cell proliferation and invasion and inhibited apoptosis caused by 5-FU, and transfection of si-FOXD3-AS1 or si-ELAVL1 in exosome-incubated A549 cells reversed these effects. Moreover, exosome-incubated A549 cells were co-transfected with si-FOXD3-AS1 and pcDNA-ELAVL1, showing the same cell proliferation, invasion, and 5-FU resistance as those of A549 cells treated with lung cancer cell-derived exosomes alone. Mechanistic studies identified that lung cancer cell-derived exosomes activated the PI3K/Akt pathway, and transfection of si-FOXD3-AS1 or treatment with the PI3K inhibitor LY294002 reversed the activation of the PI3K/Akt axis induced by exosomes. In conclusion, our study revealed that lung cancer cell-derived exosomal FOXD3-AS1 upregulated ELAVL1 expression and activated the PI3K/Akt pathway to promote lung cancer progression. Our findings provide a new strategy for lung cancer treatment.

scholarly journals Inhibitory effect of microRNA-608 on lung cancer cell proliferation, migration, and invasion by targeting BRD4 through the JAK2/STAT3 pathway

2019 ◽  
Author(s):  
Weigang Xu ◽  
Dapeng Sun ◽  
Yanqin Wang ◽  
Xinlin Zheng ◽  
Yan Li ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Proliferation ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Migration And Invasion ◽  
Cancer Cell Proliferation ◽  
Lung Cancer Cell ◽  
Stat3 Pathway ◽  
Normal Tissues ◽  
Cancer Tissues

Lung cancer is the leading cause of cancer-related mortality around the world. This malignancy has a 5-year survival rate of 21%, because most of the patients are diagnosed in the middle or late stage of the disease when local metastasis and tumor invasion have already progressed. Therefore, the investigation of the pathogenesis of lung cancer is an issue of crucial importance. MicroRNAs (miRNAs) seem to be involved in the evolution and development of lung cancer. MicroRNA-608 is likely to be downregulated in lung cancer tissues. Regarding this, the current study involved the determination of the fundamental mechanism of microRNA-608 in the development of lung cancer. Based on the results of quantitative reverse transcription polymerase chain reaction (RT-qPCR), the expression level of microRNA-608 was downregulated in 40 lung cancer tissues, compared to that in the adjacent normal tissues. The results of dual-luciferase reporter assay revealed that bromodomain-containing protein 4 (BRD4) was the direct target of microRNA-608. Accordingly, the lung cancer tissues had an elevated expression level of BRD4, in contrast to the adjacent normal tissues. The results of Cell Counting Kit 8 assay demonstrated that the high expression of microRNA-608 notably restrained lung cancer cell proliferation. The scratch wound and transwell assays showed that the upregulation of microRNA-608 suppressed the migration and invasion of lung cancer cells. Finally, the western blot assay showed that in the microRNA-608 mimics group, the expression levels of BRD4, p-JAK2, p-STATA3, CD44, and MMP9 were significantly decreased, compared with those in the negative control miRNA mimics group. Our results indicate that high expression of microRNA-608 inhibits the proliferation, migration, and invasion of lung cancer cells by targeting BRD4 via the JAK2/STAT3 pathway.

scholarly journals HNRNP A1 Promotes Lung Cancer Cell Proliferation by Modulating VRK1 Translation

2021 ◽  
Vol 22 (11) ◽  
pp. 5506
Author(s):  
Hye Guk Ryu ◽  
Youngseob Jung ◽  
Namgyu Lee ◽  
Ji-Young Seo ◽  
Sung Wook Kim ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Proliferation ◽  
Cancer Cell ◽  
Camp Response Element Binding ◽  
Cancer Cell Proliferation ◽  
Hnrnp A1 ◽  
Lung Carcinogenesis ◽  
Lung Cancer Cell ◽  
Cis Acting

Heterogeneous nuclear ribonucleoprotein (HNRNP) A1 is the most abundant and ubiquitously expressed member of the HNRNP protein family. In recent years, it has become more evident that HNRNP A1 contributes to the development of neurodegenerative diseases. However, little is known about the underlying role of HNRNP A1 in cancer development. Here, we report that HNRNP A1 expression is significantly increased in lung cancer tissues and is negatively correlated with the overall survival of patients with lung cancer. Additionally, HNRNP A1 positively regulates vaccinia-related kinase 1 (VRK1) translation via binding directly to the 3′ untranslated region (UTR) of VRK1 mRNA, thus increasing cyclin D1 (CCND1) expression by VRK1-mediated phosphorylation of the cAMP response element–binding protein (CREB). Furthermore, HNRNP A1 binding to the cis-acting region of the 3′UTR of VRK1 mRNA contributes to increased lung cancer cell proliferation. Thus, our study unveils a novel role of HNRNP A1 in lung carcinogenesis via post-transcriptional regulation of VRK1 expression and suggests its potential as a therapeutic target for patients with lung cancer.

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