Oncolytic vaccinia virus inhibits human hepatocellular carcinoma MHCC97‐H cell proliferation via endoplasmic reticulum stress, autophagy and Wnt pathways

Jia, Xiaoyuan; Chen, Yongyi; Zhao, Xin; Lv, Chunwei; Yan, Jie

doi:10.1002/jgm.2893

Cited by 18 publications

(12 citation statements)

References 72 publications

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“…We compared our microarray data with those from other poxvirus microarray analyses presented in the literature and found differences in IFNAR signaling pathways (39,43,44,59,63,64). Additional differences between our data and data from the literature on the G-protein-coupled receptor signaling pathway (44,45) and the Wnt signaling pathway (46) were also found. The discrepancies in the results may be due to the use of different viral strains, host species, cell types, and data analysis methods and the complexity of the temporal regulation of cellular transcription during the course of infection.…”

Section: Discussionmentioning

confidence: 64%

“…We searched the literature and found one microarray study by Guerra et al showing activation of the adenosine A2a receptor by WR infection in HeLa cells (44), whereas another study, by Leao-Ferreira et al, described that activation of the G-protein-coupled receptor inhibited vaccinia virus growth in BSC40 cells (45). Literature searches also found a study by Jia et al showing that vaccinia virus infections inhibits the Wnt signaling pathway in tumor cells (46).…”

Section: Resultsmentioning

confidence: 99%

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Differential Innate Immune Signaling in Macrophages by Wild-Type Vaccinia Mature Virus and a Mutant Virus with a Deletion of the A26 Protein

Kasani

Cheng

Yeh

et al. 2017

J Virol

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The Western Reserve (WR) strain of mature vaccinia virus contains an A26 envelope protein that mediates virus binding to cell surface laminin and subsequent endocytic entry into HeLa cells. Removal of the A26 protein from the WR strain mature virus generates a mutant, WRΔA26, that enters HeLa cells through plasma membrane fusion. Here, we infected murine bone marrow-derived macrophages (BMDM) with wild-type strain WR and the WRΔA26 mutant and analyzed viral gene expression and cellular innate immune signaling. In contrast to previous studies, in which both HeLa cells infected with WR and HeLa cells infected with WRΔA26 expressed abundant viral late proteins, we found that WR expressed much less viral late protein than WRΔA26 in BMDM. Microarray analysis of the cellular transcripts in BMDM induced by virus infection revealed that WR preferentially activated type 1 interferon receptor (IFNAR)-dependent signaling but WRΔA26 did not. We consistently detected a higher level of soluble beta interferon secretion and phosphorylation of the STAT1 protein in BMDM infected with WR than in BMDM infected with WRΔA26. When IFNAR-knockout BMDM were infected with WR, late viral protein expression increased, confirming that IFNAR-dependent signaling was differentially induced by WR and, in turn, restricted viral late gene expression. Finally, wild-type C57BL/6 mice were more susceptible to mortality from WRΔA26 infection than to that from WR infection, whereas IFNAR-knockout mice were equally susceptible to WR and WRΔA26 infection, demonstrating that the ability of WRΔA26 to evade IFNAR signaling has an important influence on viral pathogenesis The vaccinia virus A26 protein was previously shown to mediate virus attachment and to regulate viral endocytosis. Here, we show that infection with strain WR induces a robust innate immune response that activates type 1 interferon receptor (IFNAR)-dependent cellular genes in BMDM, whereas infection with the WRΔA26 mutant does not. We further demonstrated that the differential activation of IFNAR-dependent cellular signaling between WR and WRΔA26 not only is important for differential host restriction in BMDM but also is important for viral virulence Our study reveals a new property of WRΔA26, which is in regulating host antiviral innate immunity and.

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Section: Discussionmentioning

confidence: 64%

Section: Resultsmentioning

confidence: 99%

Differential Innate Immune Signaling in Macrophages by Wild-Type Vaccinia Mature Virus and a Mutant Virus with a Deletion of the A26 Protein

Kasani

Cheng

Yeh

et al. 2017

J Virol

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“…During ER stress, the expression of GRP78, CHOP, and ATF6 increases [21]. Recent studies have shown that the Wnt/β-catenin pathway can affect ER stress; in cancer cells, inhibition of the Wnt/β-catenin pathway induces ER stress, which then leads to apoptosis [35,36]. Furthermore, Zhang et al proposed that inhibiting the Wnt/β-catenin pathway and β-catenin degradation reverses the inhibition of ATF6 by LEF1, resulting in ATF6-induced ER stress in preadipocytes [37].…”

Section: Discussionmentioning

confidence: 99%

Simvastatin Attenuates H2O2-Induced Endothelial Cell Dysfunction by Reducing Endoplasmic Reticulum Stress

Liu

et al. 2019

Molecules

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Atherosclerosis is the pathological basis of cardiovascular disease, whilst endothelial dysfunction (ED) plays a primary role in the occurrence and development of atherosclerosis. Simvastatin has been shown to possess significant anti-atherosclerosis activity. In this study, we evaluated the protective effect of simvastatin on endothelial cells under oxidative stress and elucidated its underlying mechanisms. Simvastatin was found to attenuate H2O2-induced human umbilical vein endothelial cells (HUVECs) dysfunction and inhibit the Wnt/β-catenin pathway; however, when this pathway was activated by lithium chloride, endothelial dysfunction was clearly enhanced. Further investigation revealed that simvastatin did not alter the expression or phosphorylation of LRP6, but reduced intracellular cholesterol deposition and inhibited endoplasmic reticulum (ER) stress. Inducing ER stress with tunicamycin activated the Wnt/β-catenin pathway, whereas reducing ER stress with 4-phenylbutyric acid inhibited it. We hypothesize that simvastatin does not affect transmembrane signal transduction in the Wnt/β-catenin pathway, but inhibits ER stress by reducing intracellular cholesterol accumulation, which blocks intracellular signal transduction in the Wnt/β-catenin pathway and ameliorates endothelial dysfunction.

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“…OVs have been used in combination with conventional agents that specifically target cancer cell signaling pathways [62,63,64,65,66,67,68]. Recently, combining OVs with existing immunotherapies such as immuno-oncology agents targeting different checkpoint pathways have been investigated in both preclinical studies and clinical trials [7,8,25,26,69].…”

Section: Combination Strategies Using Oncolytic Virus and Chemicalmentioning

confidence: 99%

Targeting Autophagy for Oncolytic Immunotherapy

Jiang

Ding

et al. 2017

Biomedicines

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Oncolytic viruses (OVs) are capable of exerting anti-cancer effects by a variety of mechanisms, including immune-mediated tumor cell death, highlighting their potential use in immunotherapy. Several adaptation mechanisms such as autophagy contribute to OV-mediated anti-tumor properties. Autophagy regulates immunogenic signaling during cancer therapy which can be utilized to design therapeutic combinations using approaches that either induce or block autophagy to potentiate the therapeutic efficacy of OVs. In this article, we review the complicated interplay between autophagy, cancer, immunity, and OV, summarize recent progress in the contribution of OV-perturbed autophagy to oncolytic immunity, and discuss the challenges in targeting autophagy to enhance oncolytic immunotherapy.

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Oncolytic vaccinia virus inhibits human hepatocellular carcinoma MHCC97‐H cell proliferation via endoplasmic reticulum stress, autophagy and Wnt pathways

Abstract: The results of the present study provide new insights into the mechanisms of VV-induced tumor cell death. The engineered recombinant VV containing optimized therapeutic transgenes may represent a new avenue for cancer gene therapy. Copyright © 2016 John Wiley & Sons, Ltd.

Cited by 18 publications

References 72 publications

Differential Innate Immune Signaling in Macrophages by Wild-Type Vaccinia Mature Virus and a Mutant Virus with a Deletion of the A26 Protein

Differential Innate Immune Signaling in Macrophages by Wild-Type Vaccinia Mature Virus and a Mutant Virus with a Deletion of the A26 Protein

Simvastatin Attenuates H2O2-Induced Endothelial Cell Dysfunction by Reducing Endoplasmic Reticulum Stress

Targeting Autophagy for Oncolytic Immunotherapy

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