scholarly journals CXCR4 promotes gefitinib resistance of Huh7 cells by activating the c‐Met signaling pathway

FEBS Open Bio ◽  
2021 ◽  
Author(s):  
Dali Zhao ◽  
Zhiqiang Yang ◽  
Chen Chen ◽  
Zhipeng Zhang ◽  
Yangsheng Yu ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Huh7 Cells ◽  
Gefitinib Resistance

scholarly journals Hepatitis C Virus Infection Is Inhibited by a Noncanonical Antiviral Signaling Pathway Targeted by NS3-NS4A

2019 ◽  
Vol 93 (23) ◽  
Author(s):  
Christine Vazquez ◽  
Chin Yee Tan ◽  
Stacy M. Horner
Keyword(s):  
Hepatitis C ◽  
Viral Replication ◽  
Signaling Pathway ◽  
Transmembrane Domain ◽  
Innate Immune ◽  
Hcv Infection ◽  
Interferon Induction ◽  
Innate Immune Signaling ◽  
Huh7 Cells ◽  
Irf3 Activation

ABSTRACT The hepatitis C virus (HCV) NS3-NS4A protease complex is required for viral replication and is the major viral innate immune evasion factor. NS3-NS4A evades antiviral innate immunity by inactivating several proteins, including MAVS, the signaling adaptor for RIG-I and MDA5, and Riplet, an E3 ubiquitin ligase that activates RIG-I. Here, we identified a Tyr-16-Phe (Y16F) change in the NS4A transmembrane domain that prevents NS3-NS4A targeting of Riplet but not MAVS. This Y16F substitution reduces HCV replication in Huh7 cells, but not in Huh-7.5 cells, known to lack RIG-I signaling. Surprisingly, deletion of RIG-I in Huh7 cells did not restore Y16F viral replication. Rather, we found that Huh-7.5 cells lack Riplet expression and that the addition of Riplet to these cells reduced HCV Y16F replication, whereas the addition of Riplet lacking the RING domain restored HCV Y16F replication. In addition, TBK1 inhibition or IRF3 deletion in Huh7 cells was sufficient to restore HCV Y16F replication, and the Y16F protease lacked the ability to prevent IRF3 activation or interferon induction. Taken together, these data reveal that the NS4A Y16 residue regulates a noncanonical Riplet-TBK1-IRF3-dependent, but RIG-I-MAVS-independent, signaling pathway that limits HCV infection. IMPORTANCE The HCV NS3-NS4A protease complex facilitates viral replication by cleaving and inactivating the antiviral innate immune signaling proteins MAVS and Riplet, which are essential for RIG-I activation. NS3-NS4A therefore prevents IRF3 activation and interferon induction during HCV infection. Here, we uncover an amino acid residue within the NS4A transmembrane domain that is essential for inactivation of Riplet but does not affect MAVS cleavage by NS3-NS4A. Our study reveals that Riplet is involved in a RIG-I- and MAVS-independent signaling pathway that activates IRF3 and that this pathway is normally inactivated by NS3-NS4A during HCV infection. Our study selectively uncouples these distinct regulatory mechanisms within NS3-NS4A and defines a new role for Riplet in the antiviral response to HCV. Since Riplet is known to be inhibited by other RNA viruses, such as such influenza A virus, this innate immune signaling pathway may also be important in controlling other RNA virus infections.

scholarly journals PLAUR Confers Resistance to Gefitinib Through EGFR/P-AKT/Survivin Signaling Pathway

2018 ◽  
Vol 47 (5) ◽  
pp. 1909-1924 ◽  
Author(s):  
Jian Zhou ◽  
Kwang Joo Kwak ◽  
Zuoren Wu ◽  
Dawei Yang ◽  
Jing Li ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Membrane Potential ◽  
Tyrosine Kinase ◽  
Lung Adenocarcinoma ◽  
Signaling Pathway ◽  
Cell Apoptosis ◽  
Mitochondrial Membrane ◽  
Human Lung ◽  
Nsclc Patients ◽  
Gefitinib Resistance

Background/Aims: Tyrosine kinase inhibitor gefitinib significantly improves the survival of patients with non-small-cell lung cancer (NSCLC) by inhibiting epidermal growth factor receptor (EGFR) tyrosine kinase. However, patients eventually develop resistance to gefitinib through uncharacterized mechanisms. It is known that plasminogen activator urokinase receptor (PLAUR) plays an important role in cell proliferation, migration and apoptosis. However, the role of PLAUR, particularly exosomal PLAUR in gefitinib resistance in NSCLC has not been reported. The aim of this study is to determine the relationship between PLAUR and gefitinib resistance. Methods: In this study, a tethered cationic lipoplex nanoparticle (TCLN) biochip containing molecular beacons was used as probes to detect PLAUR mRNA in plasma exosomes from patients with gefitinib-sensitive and -resistant NSCLC. In vitro, Real-time PCR was used to examine the expression of PLAUR mRNA and Western blot was applied to examine the expression of related proteins. The gene knockdown was achieved by Lentivirus based RNA silence technique. The cell counting kit-8 assay and EdU incorporation were used to examine cell proliferation. The flow cytometry was applied to determine cell apoptosis and cell cycle, while the mitochondrial membrane potential was measured by JC-1 dye assay. Signaling pathway affected by PLAUR knockdown was identified by cDNA Microarray. The effect of PLAUR knockdown on tumorigenesis was analyzed in vivo. Results: We found that the exosomal PLAUR mRNA in the plasma of gefitinib-resistant NSCLC patients was significantly increased compared to that of gefitinib-sensitive NSCLC patients. The PLAUR mRNA and soluble PLAUR protein were also significantly increased in gefitinib-resistant human lung adenocarcinoma PC9R cells compared to gefitinib-sensitive PC9 cells. Silencing PLAUR in PC9R cells impaired mitochondrial membrane potential and increased cell apoptosis via EGFR/p-AKT/survivin signaling pathway. Furthermore, EGFR was upregulated in the geftinib-resistant PC9R cells, and knockdown of EGFR significantly increased cell apoptosis. Conclusions: Taken together, our results demonstrated that PLAUR induces geftinib-resistance through EGFR/p-AKT/survivin signaling pathway in gefitinib-resistant human lung adenocarcinoma cells. PLAUR could be a novel therapeutic target for gefitinib-resistant NSCLC patients.

scholarly journals Glycerol kinase 5 confers gefitinib resistance through SREBP1/SCD1 signaling pathway

2019 ◽  
Vol 38 (1) ◽  
Author(s):  
Jian Zhou ◽  
Guimei Qu ◽  
Ge Zhang ◽  
Zuoren Wu ◽  
Jing Liu ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Glycerol Kinase ◽  
Gefitinib Resistance

scholarly journals 4-Hydroxyderricin Promotes Apoptosis and Cell Cycle Arrest through Regulating PI3K/AKT/mTOR Pathway in Hepatocellular Cells

Foods ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2036
Author(s):  
Xiang Gao ◽  
Yuhuan Jiang ◽  
Qi Xu ◽  
Feng Liu ◽  
Xuening Pang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Signaling Pathway ◽  
Mtor Signaling ◽  
Flavonoid Compound ◽  
Mtor Signaling Pathway ◽  
Promoting Effect ◽  
Cycle Arrest ◽  
Huh7 Cells ◽  
Hcc Cells

4-hydroxyderricin (4-HD), as a natural flavonoid compound derived from Angelica keiskei, has largely unknown inhibition and mechanisms on liver cancer. Herein, we investigated the inhibitory effects of 4-HD on hepatocellular carcinoma (HCC) cells and clarified the potential mechanisms by exploring apoptosis and cell cycle arrest mediated via the PI3K/AKT/mTOR signaling pathway. Our results show that 4-HD treatment dramatically decreased the survival rate and activities of HepG2 and Huh7 cells. The protein expressions of apoptosis-related genes significantly increased, while those related to the cell cycle were decreased by 4-HD. 4-HD also down-regulated PI3K, p-PI3K, p-AKT, and p-mTOR protein expression. Moreover, PI3K inhibitor (LY294002) enhanced the promoting effect of 4-HD on apoptosis and cell cycle arrest in HCC cells. Consequently, we demonstrate that 4-HD can suppress the proliferation of HCC cells by promoting the PI3K/AKT/mTOR signaling pathway mediated apoptosis and cell cycle arrest.

scholarly journals Hepatitis C virus infection is inhibited by a non-canonical antiviral signaling pathway targeted by NS3-NS4A

2019 ◽  
Author(s):  
Christine Vazquez ◽  
Chin Yee Tan ◽  
Stacy M. Horner
Keyword(s):  
Hepatitis C ◽  
Viral Replication ◽  
Signaling Pathway ◽  
Transmembrane Domain ◽  
Innate Immune ◽  
Hcv Infection ◽  
Interferon Induction ◽  
Innate Immune Signaling ◽  
Huh7 Cells ◽  
Irf3 Activation

AbstractThe hepatitis C virus (HCV) NS3-NS4A protease complex is required for viral replication and is the major viral innate immune evasion factor. NS3-NS4A evades antiviral innate immunity by inactivating several proteins, including MAVS, the signaling adaptor for RIG-I and MDA5, and Riplet, an E3 ubiquitin ligase that activates RIG-I. Here, we identified a Tyr-16-Phe (Y16F) change in the NS4A transmembrane domain that prevents NS3-NS4A targeting of Riplet but not MAVS. This Y16F substitution reduces HCV replication in Huh7 cells, but not in Huh-7.5 cells, known to lack RIG-I signaling. Surprisingly, deletion of RIG-I in Huh7 cells did not restore Y16F viral replication. Rather, we found that Huh-7.5 cells lack Riplet expression and that addition of Riplet to these cells reduced HCV Y16F replication. In addition, IRF3 deletion in Huh7 cells was sufficient to restore HCV Y16F replication, and the Y16F protease lacked the ability to prevent IRF3 activation or interferon induction. Taken together, these data reveal that the NS4A Y16 residue regulates a non-canonical Riplet-IRF3-dependent, but RIG-I-MAVS-independent, signaling pathway that limits HCV infection.ImportanceThe HCV NS3-NS4A protease complex facilitates viral replication by cleaving and inactivating the antiviral innate immune signaling proteins MAVS and Riplet, which are essential for RIG-I activation. NS3-NS4A therefore prevents IRF3 activation and interferon induction during HCV infection. Here, we uncover an amino acid residue within the NS4A transmembrane domain that is essential for inactivation of Riplet, but does not affect MAVS cleavage by NS3-NS4A. Our study reveals that Riplet is involved in a RIG-I- and MAVS-independent signaling pathway that activates IRF3 and that this pathway is normally inactivated by NS3-NS4A during HCV infection. Our study selectively uncouples these distinct regulatory mechanisms within NS3-NS4A and defines a new role for Riplet in the antiviral response to HCV. As Riplet is known to be inhibited by other RNA viruses, such as such influenza A virus, this innate immune signaling pathway may also be important in controlling other RNA virus infections.

scholarly journals The Ebola virus soluble glycoprotein contributes to viral pathogenesis by activating the MAP kinase signaling pathway

2021 ◽  
Vol 17 (9) ◽  
pp. e1009937
Author(s):  
Wakako Furuyama ◽  
Kyle Shifflett ◽  
Heinz Feldmann ◽  
Andrea Marzi
Keyword(s):  
Signaling Pathway ◽  
Ebola Virus ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Hek293 Cells ◽  
Huh7 Cells ◽  
Mitogen Activated Protein

Ebola virus (EBOV) expresses three different glycoproteins (GPs) from its GP gene. The primary product, soluble GP (sGP), is secreted in abundance during infection. EBOV sGP has been discussed as a potential pathogenicity factor, however, little is known regarding its functional role. Here, we analyzed the role of sGP in vitro and in vivo. We show that EBOV sGP has two different functions that contribute to infectivity in tissue culture. EBOV sGP increases the uptake of virus particles into late endosomes in HEK293 cells, and it activates the mitogen-activated protein kinase (MAPK) signaling pathway leading to increased viral replication in Huh7 cells. Furthermore, we analyzed the role of EBOV sGP on pathogenicity using a well-established mouse model. We found an sGP-dependent significant titer increase of EBOV in the liver of infected animals. These results provide new mechanistic insights into EBOV pathogenicity and highlight EBOV sGP as a possible therapeutic target.

Aurora-A promotes gefitinib resistance via a NF-κB signaling pathway in p53 knockdown lung cancer cells

2011 ◽  
Vol 405 (2) ◽  
pp. 168-172 ◽  
Author(s):  
Chun Chi Wu ◽  
Chang-Tze Ricky Yu ◽  
Gee-Chen Chang ◽  
Jin-Mei Lai ◽  
Shih-Lan Hsu
Keyword(s):  
Lung Cancer ◽  
Cancer Cells ◽  
Signaling Pathway ◽  
Lung Cancer Cells ◽  
Aurora A ◽  
Gefitinib Resistance

scholarly journals NNT-AS1 Impairs CD4+ T Cells Infiltration by Up-Regulating TGF-β Signaling in Hepatocellular Carcinoma

2020 ◽  
Author(s):  
Yakun Wang ◽  
Lei Yang ◽  
Xichen Dong ◽  
Xin Yang ◽  
Xinxue Zhang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
T Cells ◽  
Signaling Pathway ◽  
Quantitative Pcr ◽  
T Lymphocyte ◽  
Immunological Response ◽  
Normal Tissues ◽  
Prognostic Analysis ◽  
Huh7 Cells ◽  
Pcr Assays

Abstract Background Nicotinamide Nucleotide Transhydrogenase-antisense RNA1 (NNT-AS1) is one of long non coding RNA, has been shown with high levels in several types of cancers. However, the molecular mechanism remains to be revealed for NNT-AS1 in the progession of hepatocellular carcinoma (HCC). TGF-β signaling pathway has been identified as one of negative factor for excessive immunological response. We sought to investigate the effects of NNT-AS1 mediating T cells infiltration by regulating TGF-β signaling pathway in patients with HCC.Methods RNAscope In Situ Hybridization and Real Time Quantitative PCR assays were applied to detect NNT-AS1 levels in HCC tissues. Immunohistochemistry (IHC) assays were used to observe the co-expressions of TGF-β, TGFBR1, SMAD1/5/9, and CD4+ T cells. The mechanisms as to how NNT-AS1 orchestrates TGF-β signaling were further explored in HepG2 and Huh7 cells. Results RNA-scope analyses revealed that the levels of NNT-AS1 were significant higher in cancerous tissues than in paired non-cancerous tissues (P=0.0001). Quantitative PCR assays validated the high expression of NNT-AS1 in HCC cancer tissues (n=64) when compared with normal tissues (n=26) (P=0.0003). The prognostic analysis indicated that the OS rates for HCC patients with high levels of NNT-AS1 were significantly lower than patients with low levels of NNT-AS1 (P=0.0402). Mechanistic analysis demonstrated that the downregulation of NNT-AS1 significantly reduced the expression of TGF-β, TGFBR1, and SMAD5. Moreover, the inhibition of NNT-AS1 decrease the expression of TGF-β，TGFBR1, and SMAD5. Importantly, IHC analyses indicated that the levels of NNT-AS1 were negatively correlated with CD4+ T lymphocyte cells infiltration in tissues from 16 HCC patients.Conclusions Our study depicts a novel mechanism regarding NNT-AS1 activates TGF-β signaling pathway and thus impairs the CD4+ T lymphocyte cells infiltration in HCC.

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