Interferon-β Induces Cellular Senescence in Cutaneous Human Papilloma Virus-Transformed Human Keratinocytes by Affecting p53 Transactivating Activity

Chiantore, Maria Vincenza; Vannucchi, Serena; Accardi, Rosita; Tommasino, Massimo; Percario, Zulema Antonia; Vaccari, Gabriele; Affabris, Elisabetta; Fiorucci, Gianna; Romeo, Giovanna

doi:10.1371/journal.pone.0036909

Cited by 35 publications

(25 citation statements)

References 50 publications

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“…The gene transfer of both p19Arf and IFNβ was able to increase cell death and decrease viability of LLC1 cells. In fact, a few groups have described interaction of p53 and type I interferon pathways [28], [52], [53], [54], providing additional opportunities for interplay between endogenous p53 and IFNβ for the induction of cell death and immune activation.…”

Section: Discussionmentioning

confidence: 99%

Intratumoral Immunization by p19Arf and Interferon-β Gene Transfer in a Heterotopic Mouse Model of Lung Carcinoma

Catani

Medrano

Hunger

et al. 2016

Translational Oncology

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Therapeutic strategies that act by eliciting and enhancing antitumor immunity have been clinically validated as an effective treatment modality but may benefit from the induction of both cell death and immune activation as primary stimuli. Using our AdRGD-PG adenovector platform, we show here for the first time that in situ gene transfer of p19Arf and interferon-β (IFNβ) in the LLC1 mouse model of lung carcinoma acts as an immunotherapy. Although p19Arf is sufficient to induce cell death, only its pairing with IFNβ significantly induced markers of immunogenic cell death. In situ gene therapy with IFNβ, either alone or in combination with p19Arf, could retard tumor progression, but only the combined treatment was associated with a protective immune response. Specifically in the case of combined intratumoral gene transfer, we identified 167 differentially expressed genes when using microarray to evaluate tumors that were treated in vivo and confirmed the activation of CCL3, CXCL3, IL1α, IL1β, CD274, and OSM, involved in immune response and chemotaxis. Histologic evaluation revealed significant tumor infiltration by neutrophils, whereas functional depletion of granulocytes ablated the antitumor effect of our approach. The association of in situ gene therapy with cisplatin resulted in synergistic elimination of tumor progression. In all, in situ gene transfer with p19Arf and IFNβ acts as an immunotherapy involving recruitment of neutrophils, a desirable but previously untested outcome, and this approach may be allied with chemotherapy, thus providing significant antitumor activity and warranting further development for the treatment of lung carcinoma.

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Section: Discussionmentioning

confidence: 99%

Intratumoral Immunization by p19Arf and Interferon-β Gene Transfer in a Heterotopic Mouse Model of Lung Carcinoma

Catani

Medrano

Hunger

et al. 2016

Translational Oncology

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“…131 In various settings, interferon-triggered cancer cell apoptosis or senescence involves PML and p53. [132][133][134][135][136] Similarly, both PML and sumoylation of DAXX were shown to be critical for interferon-triggered apoptosis in B cells. 137 Thus, the PML interferon crosstalks are not limited to antiviral effects.…”

Section: The Interferon Connection and Medical Implicationsmentioning

confidence: 99%

PML nuclear bodies: Assembly and oxidative stress-sensitive sumoylation

Şahin¹,

Lallemand-Breitenbach²

2014

Nucleus

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“…Exogenous IFN-I is sufficient to suppress transformation and can induce senescence by upregulation of cyclin-dependent kinase inhibitors p15, p21, and p27 [38,60,61]. Furthermore, IFN-I signaling increases in MEFs as they approach senescence, with late passage MEFs producing higher basal levels of IFN-β than early passage MEFs [17].…”

Section: Effect Of Immortalization On Antiviral Signalingmentioning

confidence: 99%

The Importance of Physiologically Relevant Cell Lines for Studying Virus–Host Interactions

Hare

Collins

Cuddington

et al. 2016

Viruses

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Viruses interact intimately with the host cell at nearly every stage of replication, and the cell model that is chosen to study virus infection is critically important. Although primary cells reflect the phenotype of healthy cells in vivo better than cell lines, their limited lifespan makes experimental manipulation challenging. However, many tumor-derived and artificially immortalized cell lines have defects in induction of interferon-stimulated genes and other antiviral defenses. These defects can affect virus replication, especially when cells are infected at lower, more physiologically relevant, multiplicities of infection. Understanding the selective pressures and mechanisms underlying the loss of innate signaling pathways is helpful to choose immortalized cell lines without impaired antiviral defense. We describe the trials and tribulations we encountered while searching for an immortalized cell line with intact innate signaling, and how directed immortalization of primary cells avoids many of the pitfalls of spontaneous immortalization.

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Interferon-β Induces Cellular Senescence in Cutaneous Human Papilloma Virus-Transformed Human Keratinocytes by Affecting p53 Transactivating Activity

Cited by 35 publications

References 50 publications

Intratumoral Immunization by p19Arf and Interferon-β Gene Transfer in a Heterotopic Mouse Model of Lung Carcinoma

Intratumoral Immunization by p19Arf and Interferon-β Gene Transfer in a Heterotopic Mouse Model of Lung Carcinoma

PML nuclear bodies: Assembly and oxidative stress-sensitive sumoylation

The Importance of Physiologically Relevant Cell Lines for Studying Virus–Host Interactions

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