scholarly journals Diversity of cell death signaling pathways in macrophages upon infection with modified vaccinia virus Ankara (MVA)

2021 ◽  
Vol 12 (11) ◽  
Author(s):  
Lioba Klaas ◽  
Juliane Vier ◽  
Ian E. Gentle ◽  
Georg Häcker ◽  
Susanne Kirschnek
Keyword(s):  
Cell Death ◽  
Vaccinia Virus ◽  
Signaling Pathways ◽  
Target Cells ◽  
Specific Cell ◽  
Substantial Impact ◽  
Cell Death Pathways ◽  
Modified Vaccinia Virus Ankara ◽  
Cell Death Signaling ◽  
Induced Apoptosis

AbstractRegulated cell death frequently occurs upon infection by intracellular pathogens, and extent and regulation is often cell-type-specific. We aimed to identify the cell death-signaling pathways triggered in macrophages by infection with modified vaccinia virus Ankara (MVA), an attenuated strain of vaccinia virus used in vaccination. While most target cells seem to be protected by antiapoptotic proteins encoded in the MVA genome, macrophages die when infected with MVA. We targeted key signaling components of specific cell death-pathways and pattern recognition-pathways using genome editing and small molecule inhibitors in an in vitro murine macrophage differentiation model. Upon infection with MVA, we observed activation of mitochondrial and death-receptor-induced apoptosis-pathways as well as the necroptosis-pathway. Inhibition of individual pathways had a little protective effect but led to compensatory death through the other pathways. In the absence of mitochondrial apoptosis, autocrine/paracrine TNF-mediated apoptosis and, in the absence of caspase-activity, necroptosis occurred. TNF-induction depended on the signaling molecule STING, and MAVS and ZBP1 contributed to MVA-induced apoptosis. The mode of cell death had a substantial impact on the cytokine response of infected cells, indicating that the immunogenicity of a virus may depend not only on its PAMPs but also on its ability to modulate individual modalities of cell death. These findings provide insights into the diversity of cell death-pathways that an infection can trigger in professional immune cells and advance our understanding of the intracellular mechanisms that govern the immune response to a virus.

scholarly journals Non-Apoptotic Cell Death Signaling Pathways in Melanoma

2020 ◽  
Vol 21 (8) ◽  
pp. 2980 ◽  
Author(s):  
Mariusz L. Hartman
Keyword(s):  
Cell Death ◽  
Signaling Pathways ◽  
Melanoma Cell ◽  
Apoptotic Cell ◽  
Genetic Alterations ◽  
Melanoma Cells ◽  
Apoptotic Cell Death ◽  
Specific Cell ◽  
Anti Cancer ◽  
Cell Death Signaling

Resisting cell death is a hallmark of cancer. Disturbances in the execution of cell death programs promote carcinogenesis and survival of cancer cells under unfavorable conditions, including exposition to anti-cancer therapies. Specific modalities of regulated cell death (RCD) have been classified based on different criteria, including morphological features, biochemical alterations and immunological consequences. Although melanoma cells are broadly equipped with the anti-apoptotic machinery and recurrent genetic alterations in the components of the RAS/RAF/MEK/ERK signaling markedly contribute to the pro-survival phenotype of melanoma, the roles of autophagy-dependent cell death, necroptosis, ferroptosis, pyroptosis, and parthanatos have recently gained great interest. These signaling cascades are involved in melanoma cell response and resistance to the therapeutics used in the clinic, including inhibitors of BRAFmut and MEK1/2, and immunotherapy. In addition, the relationships between sensitivity to non-apoptotic cell death routes and specific cell phenotypes have been demonstrated, suggesting that plasticity of melanoma cells can be exploited to modulate response of these cells to different cell death stimuli. In this review, the current knowledge on the non-apoptotic cell death signaling pathways in melanoma cell biology and response to anti-cancer drugs has been discussed.

scholarly journals FKBP51 Affects TNF-Related Apoptosis Inducing Ligand Response in Melanoma

2021 ◽  
Vol 9 ◽  
Author(s):  
Martina Tufano ◽  
Elena Cesaro ◽  
Rosanna Martinelli ◽  
Roberto Pacelli ◽  
Simona Romano ◽  
...  
Keyword(s):  
Cell Death ◽  
Immune Cells ◽  
Histone Deacetylases ◽  
Melanoma Cells ◽  
Transcriptional Level ◽  
Cell Death Pathways ◽  
Yin Yang 1 ◽  
Immune Precipitation ◽  
Induced Apoptosis ◽  
Repressor Activity

Melanoma is one of the most immunogenic tumors and has the highest potential to elicit specific adaptive antitumor immune responses. Immune cells induce apoptosis of cancer cells either by soluble factors or by triggering cell-death pathways. Melanoma cells exploit multiple mechanisms to escape immune system tumoricidal control. FKBP51 is a relevant pro-oncogenic factor of melanoma cells supporting NF-κB-mediated resistance and cancer stemness/invasion epigenetic programs. Herein, we show that FKBP51-silencing increases TNF-related apoptosis-inducing ligand (TRAIL)-R2 (DR5) expression and sensitizes melanoma cells to TRAIL-induced apoptosis. Consistent with the general increase in histone deacetylases, as by the proteomic profile, the immune precipitation assay showed decreased acetyl-Yin Yang 1 (YY1) after FKBP51 depletion, suggesting an impaired repressor activity of this transcription factor. ChIP assay supported this hypothesis. Compared with non-silenced cells, a reduced acetyl-YY1 was found on the DR5 promoter, resulting in increased DR5 transcript levels. Using Crispr/Cas9 knockout (KO) melanoma cells, we confirmed the negative regulation of DR5 by FKBP51. We also show that KO cells displayed reduced levels of acetyl-EP300 responsible for YY1 acetylation, along with reduced acetyl-YY1. Reconstituting FKBP51 levels contrasted the effects of KO on DR5, acetyl-YY1, and acetyl-EP300 levels. In conclusion, our finding shows that FKBP51 reduces DR5 expression at the transcriptional level by promoting YY1 repressor activity. Our study supports the conclusion that targeting FKBP51 increases the expression level of DR5 and sensitivity to TRAIL-induced cell death, which can improve the tumoricidal action of immune cells.

scholarly journals Tracking Modified Vaccinia Virus Ankara in the Chicken Embryo: In Vivo Tropism and Pathogenesis of Egg Infections

Viruses ◽  
2018 ◽  
Vol 10 (9) ◽  
pp. 452 ◽  
Author(s):  
Martin Langenmayer ◽  
Anna-Theresa Lülf-Averhoff ◽  
Silvia Adam-Neumair ◽  
Gerd Sutter ◽  
Asisa Volz
Keyword(s):  
Vaccinia Virus ◽  
Target Cells ◽  
Vaccine Platform ◽  
Fluorescent Reporter ◽  
Vector Vaccine ◽  
Embryonic Tissues ◽  
Modified Vaccinia Virus Ankara ◽  
Chicken Eggs ◽  
Embryonated Chicken

The Modified Vaccinia virus Ankara (MVA) is a highly attenuated vaccinia virus serving as a promising vector vaccine platform to develop vaccines against infectious diseases. In contrast to the well-established replication deficiency and safety of MVA in mammals, much less is known about MVA infection in avian hosts. Here, we used a recombinant MVA expressing fluorescent reporter proteins under transcriptional control of specific viral early and late promoters to study in vivo tropism, distribution, and pathogenesis of MVA infections in embryonated chicken eggs. The chorioallantoic membrane (CAM) of embryonated chicken eggs was inoculated with recombinant MVA, MVA or phosphate-buffered saline. The infection was analyzed by fluorescence microscopy, histology, immunohistochemistry, and virus titration of embryonic tissues. After infection of the CAM, MVA spread to internal and external embryonic tissues with the liver as a major target organ. Macrophages and hematopoietic cells were identified as primary target cells of MVA infection and may be involved in virus spread. Increasing doses of MVA did not result in increased lesion severity or embryonic death. Despite MVA generalization to embryonic tissues, the CAM seems to be the major site of MVA replication. The absence of considerable organ lesions and MVA-associated mortality highlights an excellent safety profile of MVA in chicken hosts.

scholarly journals Use of human neuroblastoma SH-SY5Y cells to evaluate glyphosate-induced effects on oxidative stress, neuronal development and cell death signaling pathways

2020 ◽  
Vol 135 ◽  
pp. 105414 ◽  
Author(s):  
María-Aránzazu Martínez ◽  
José-Luis Rodríguez ◽  
Bernardo Lopez-Torres ◽  
Marta Martínez ◽  
María-Rosa Martínez-Larrañaga ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Signaling Pathways ◽  
Neuronal Development ◽  
Human Neuroblastoma ◽  
Cell Death Signaling

Caspase-dependent and -independent pathways for cadmium-induced apoptosis in cultured kidney proximal tubule cells

2006 ◽  
Vol 291 (4) ◽  
pp. F823-F832 ◽  
Author(s):  
Wing-Kee Lee ◽  
Marouan Abouhamed ◽  
Frank Thévenod
Keyword(s):  
Cell Death ◽  
Proximal Tubule ◽  
Rat Kidney ◽  
Cadmium Concentration ◽  
Nuclear Staining ◽  
Kidney Proximal Tubule ◽  
Cell Death Pathways ◽  
Cyt C ◽  
Induced Apoptosis ◽  
Apoptosis Inducing Factor

The nephrotoxic metal cadmium at micromolar concentrations induces apoptosis of rat kidney proximal tubule (PT) cells within 3–6 h of exposure. The underlying cell death pathways remain poorly defined. Using Hoechst 33342/ethidium bromide nuclear staining and 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) cell death assays, 10–50 μM cadmium induced apoptosis of immortalized rat kidney cells derived from the S1-segment of PT at 6 and 24 h, but necrosis at 24 h only. Cadmium (10–50 μM) also caused mitochondrial cytochrome c (cyt. c)- and apoptosis-inducing factor release at 24 h, but not at 6 h, as measured by immunofluorescence imaging and immunoblotting. Caspases-9 and -3 were activated only by 10 μM cadmium for 24 h, and accordingly apoptosis was significantly reduced by the respective inhibitors (z-LEHD-fmk, z-DEVD-fmk; 10 μg/ml) at 24 h, but not at 6 h, without affecting necrosis. At 6 h, 10 μM cadmium increased the activity of the calcium-activated protease calpain, but not at 24 h, and calpain inhibitors (ALLN, PD 150606; 10–30 μM) blocked apoptosis by 10 μM cadmium at 3–6 h. However, PD-150606 also attenuated caspase-3 activity and apoptosis at 24 h, suggesting calpain-dependent caspase activation. Thus cadmium-induced apoptosis of PT cells involves a complex and sensitive interplay of signaling cascades involving mitochondrial proapoptotic factors, calpains and caspases, whose activation is also determined by cadmium concentration and the duration of cadmium exposure.

scholarly journals Varicella-Zoster Virus ORF63 Protects Human Neuronal and Keratinocyte Cell Lines from Apoptosis and Changes Its Localization upon Apoptosis Induction

2018 ◽  
Vol 92 (12) ◽  
pp. e00338-18 ◽  
Author(s):  
Chelsea Gerada ◽  
Megan Steain ◽  
Brian P. McSharry ◽  
Barry Slobedman ◽  
Allison Abendroth
Keyword(s):  
Cell Death ◽  
Varicella Zoster Virus ◽  
Gene Product ◽  
Postherpetic Neuralgia ◽  
Hacat Cells ◽  
Apoptosis Induction ◽  
Varicella Zoster ◽  
Cell Death Pathways ◽  
Keratinocyte Cell ◽  
Induced Apoptosis

ABSTRACTThere are many facets of varicella-zoster virus (VZV) pathogenesis that are not fully understood, such as the mechanisms involved in the establishment of lifelong latency, reactivation, and development of serious conditions like postherpetic neuralgia (PHN). Virus-encoded modulation of apoptosis has been suggested to play an important role in these processes. VZV open reading frame 63 (ORF63) has been shown to modulate apoptosis in a cell-type-specific manner, but the impact of ORF63 on cell death pathways has not been examined in isolation in the context of human cells. We sought to elucidate the effect of VZV ORF63 on apoptosis induction in human neuron and keratinocyte cell lines. VZV ORF63 was shown to protect differentiated SH-SY5Y neuronal cells against staurosporine-induced apoptosis. In addition, VZV infection did not induce high levels of apoptosis in the HaCaT human keratinocyte line, highlighting a delay in apoptosis induction. VZV ORF63 was shown to protect HaCaT cells against both staurosporine- and Fas ligand-induced apoptosis. Confocal microscopy was utilized to examine VZV ORF63 localization during apoptosis induction. In VZV infection and ORF63 expression alone, VZV ORF63 became more cytoplasmic, with aggregate formation during apoptosis induction. Taken together, this suggests that VZV ORF63 protects both differentiated SH-SY5Y cells and HaCaT cells from apoptosis induction and may mediate this effect through its localization change during apoptosis. VZV ORF63 is a prominent VZV gene product in both productive and latent infection and thus may play a critical role in VZV pathogenesis by aiding neuron and keratinocyte survival.IMPORTANCEVZV, a human-specific alphaherpesvirus, causes chicken pox during primary infection and establishes lifelong latency in the dorsal root ganglia (DRG). Reactivation of VZV causes shingles, which is often followed by a prolonged pain syndrome called postherpetic neuralgia. It has been suggested that the ability of the virus to modulate cell death pathways is linked to its ability to establish latency and reactivate. The significance of our research lies in investigating the ability of ORF63, a VZV gene product, to inhibit apoptosis in novel cell types crucial for VZV pathogenesis. This will allow an increased understanding of critical enigmatic components of VZV pathogenesis.

scholarly journals A Priori Activation of Apoptosis Pathways of Tumor (AAAPT) Technology: Development of Targeted Apoptosis Initiators for Cancer Treatment

2019 ◽  
Author(s):  
Raghu Pandurangi ◽  
Marco Tomasetti ◽  
Thillai Verapazham Sekar ◽  
Ramasamy Paulmurugan ◽  
Cynthia Ma ◽  
...  
Keyword(s):  
Cell Death ◽  
Cancer Cells ◽  
Technology Development ◽  
Tumor Regression ◽  
A Priori ◽  
Specific Cell ◽  
Cell Death Pathways ◽  
Survival Pathways ◽  
Apoptosis Pathways

AbstractCancer cells develop tactics to circumvent the interventions by desensitizing themselves to interventions. The principle routes of desensitization include a) activation of survival pathways (e.g. NF-kB, PARP) and b) downregulation of cell death pathways (e.g. CD95/CD95L). As a result, it requires high therapeutic dose to achieve tumor regression which, in turn damages normal cells through the collateral damaging effects. Methods are needed to sensitize the low and non-responsive resistant tumor cells including cancer stem cells (CSCs) in order to evoke a better response from the current treatments. Current treatments including chemotherapy can induce cell death only in bulk cancer cells sparing CSCs and cancer resistant cells (CRCs) which are shown to be responsible for high recurrence of disease and low patient survival. Here, we report several novel tumor targeted sensitizers derived from the natural Vitamin E analogue (AMP-001-003). The drug design is based on a novel concept “A priori activation of apoptosis pathways of tumor technology (AAAPT) which is designed to activate specific cell death pathways and inhibit survival pathways simultaneously. Our results indicate that AMP-001-003 sensitize various types of cancer cells including MDA-MB-231 (triple negative breast cancer), PC3 (prostate cancer) and A543 (ling cancer) cells resulting in reducing the IC-50 of doxorubicin in vitro. At higher dose, AMP-001 acts as an anti-tumor agent on its own. The synergy between AMP-001 and doxorubicin could pave a new pathway to use AMP-001 as a neoadjuvant to chemotherapy to achieve a better efficacy and reduced off-target toxicity by the current treatments.Summary StatementA Priori Activation of Apoptosis Pathways of Tumor often referred to as “AAAPT” is a novel targeted tumor sensitizing technology which synergizes with chemotherapy to enhance the treatment efficacy.

scholarly journals Downregulation of PUMA underlies resistance to FGFR1 inhibitors in the stem cell leukemia/lymphoma syndrome

2020 ◽  
Vol 11 (10) ◽  
Author(s):  
Yun Liu ◽  
Baohuan Cai ◽  
Yating Chong ◽  
Hualei Zhang ◽  
Chesley-Anne Kemp ◽  
...  
Keyword(s):  
Cell Death ◽  
Kinase Inhibitors ◽  
Leukemic Cells ◽  
Direct Role ◽  
Genetic Changes ◽  
Cell Death Pathways ◽  
Pten Deletion ◽  
Induced Apoptosis ◽  
Resistant Cells

Abstract Resistance to molecular therapies frequently occur due to genetic changes affecting the targeted pathway. In myeloid and lymphoid leukemias/lymphomas resulting from constitutive activation of FGFR1 kinases, resistance has been shown to be due either to mutations in FGFR1 or deletions of PTEN. RNA-Seq analysis of the resistant clones demonstrates expression changes in cell death pathways centering on the p53 upregulated modulator of apoptosis (Puma) protein. Treatment with different tyrosine kinase inhibitors (TKIs) revealed that, in both FGFR1 mutation and Pten deletion-mediated resistance, sustained Akt activation in resistant cells leads to compromised Puma activation, resulting in suppression of TKI-induced apoptosis. This suppression of Puma is achieved as a result of sequestration of inactivated p-Foxo3a in the cytoplasm. CRISPR/Cas9 mediated knockout of Puma in leukemic cells led to an increased drug resistance in the knockout cells demonstrating a direct role in TKI resistance. Since Puma promotes cell death by targeting Bcl2, TKI-resistant cells showed high Bcl2 levels and targeting Bcl2 with Venetoclax (ABT199) led to increased apoptosis in these cells. In vivo treatment of mice xenografted with resistant cells using ABT199 suppressed leukemogenesis and led to prolonged survival. This in-depth survey of the underlying genetic mechanisms of resistance has identified a potential means of treating FGFR1-driven malignancies that are resistant to FGFR1 inhibitors.

scholarly journals The target cell nucleus is not required for cell-mediated granzyme- or Fas-based cytotoxicity.

1995 ◽  
Vol 181 (5) ◽  
pp. 1905-1909 ◽  
Author(s):  
H Nakajima ◽  
P Golstein ◽  
P A Henkart
Keyword(s):  
Cell Death ◽  
Target Cell ◽  
Cytotoxic T Lymphocyte ◽  
Target Cells ◽  
Cytotoxic Lymphocytes ◽  
Cell Nuclei ◽  
Effector Cells ◽  
Cell Death Pathways ◽  
Mast Cell Tumors ◽  
Nuclear Damage

The requirement for target cell nuclei in the two apoptotic death pathways used by cytotoxic lymphocytes was tested using model effector systems in which the granzyme and Fas pathways of target damage are isolated. Mast cell tumors expressing granzymes A and B in addition to cytolysin/perforin lysed tumor target cells about 10-fold more efficiently than comparable effector cells without granzymes. Enucleated cytoplast targets derived from these cells were also lysed with a similar 10-fold effect of granzymes. In contrast to cytoplasts, effector granzyme expression did not influence lysis of red cell targets. The Fas pathway was assessed using the selected cytotoxic T lymphocyte hybridoma subline d11S, which lysed target cells expressing Fas but not those lacking Fas. Similarly, cytoplasts derived from Fas+ but not Fas- cells were also readily lysed by these effector cells. Thus, neither the nucleus itself nor the characteristic apoptotic nuclear damage associated with the two major cell death pathways used by cytotoxic lymphocytes are required for cell death per se.

Fas and other cell death signaling pathways

1997 ◽  
Vol 9 (2) ◽  
pp. 93-107 ◽  
Author(s):  
Valérie Depraetere ◽  
Pierre Golstein
Keyword(s):  
Cell Death ◽  
Signaling Pathways ◽  
Cell Death Signaling
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