TRAIL is a key target in S-phase slowing-dependent apoptosis induced by interferon-β in cervical carcinoma cells

Vannucchi, Serena; Chiantore, Maria Vincenza; Fiorucci, Gianna; Percario, Zulema Antonia; Leone, Stefano; Affabris, Elisabetta; Romeo, Giovanna

doi:10.1038/sj.onc.1208403

Cited by 21 publications

(24 citation statements)

References 37 publications

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“…This stimulates a pleiotropy of biological responses, of which antiviral activity is the most studied. In addition, interferon induces a strong antiproliferative response in many cell lines, which is a combination of cell cycle arrest (particularly S-phase arrest [47,48]) and initiation of apoptosis (49). To activate interferon-induced apoptosis, an intact JAK-STAT pathway is required (50).…”

Section: Discussionmentioning

confidence: 99%

Type I Interferons Induce Apoptosis by Balancing cFLIP and Caspase-8 Independent of Death Ligands

Apelbaum

Yarden

Warszawski

et al. 2013

Molecular and Cellular Biology

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Interferons induce a pleiotropy of responses through binding the same cell surface receptor. Here we investigated the molecular mechanism driving interferon-induced apoptosis. Using a nonbiased small interfering RNA (siRNA) screen, we show that silencing genes whose products are directly engaged in the initiation of interferon signaling completely abrogate the interferon antiproliferative response. Apoptosis-related genes such as the caspase-8, cFLIP, and DR5 genes specifically interfere with interferon-induced apoptosis, which we found to be independent of the activity of death ligands. The one gene for which silencing resulted in the strongest proapoptotic effect upon interferon signaling is the cFLIP gene, where silencing shortened the time of initiation of apoptosis from days to hours and increased dramatically the population of apoptotic cells. Thus, cFLIP serves as a regulator for interferon-induced apoptosis. A shift over time in the balance between cFLIP and caspase-8 results in downstream caspase activation and apoptosis. While gamma interferon (IFN-␥) also causes caspase-8 upregulation, we suggest that it follows a different path to apoptosis.

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Section: Discussionmentioning

confidence: 99%

Type I Interferons Induce Apoptosis by Balancing cFLIP and Caspase-8 Independent of Death Ligands

Apelbaum

Yarden

Warszawski

et al. 2013

Molecular and Cellular Biology

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“…IFN beta induces apoptosis in melanoma [21,22] and causes prolongation of cell-cycle progression via the accumulation of cells in the S phase [23] and up-regulation of TRAIL [23,24]. To test our hypothesis that the regulation of gene expression in melanoma cells activated by class I IFNs results in antitumor effects, we exposed melanoma cells to both affinity-enriched and affinity/ ion exchange-enriched MDA7/IL-24 protein preparations and measured the IFN beta in the culture supernatant by ELISA.…”

Section: Mda7/il-24 Induced Ifn Beta Secretion In Melanoma Cells Andmentioning

confidence: 99%

Killing of human melanoma cells induced by activation of class I interferon-regulated signaling pathways via MDA-7/IL-24

Ekmekçioglu

Mumm²,

Udtha

et al. 2008

Cytokine

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Restoration of the tumor-suppression function by gene transfer of the melanoma differentiationassociated gene 7 (MDA7)/interleukin 24 (IL-24) successfully induces apoptosis in melanoma tumors in vivo. To address the molecular mechanisms involved, we previously revealed that MDA7/ IL-24 treatment of melanoma cells down-regulates interferon regulatory factor (IRF)-1 expression and concomitantly up-regulates IRF-2 expression, which competes with the activity of IRF-1 and reverses the induction of IRF-1-regulated inducible nitric oxide synthase (iNOS). Interferons (IFNs) influence melanoma cell survival by modulating apoptosis. A class I IFN (IFN alfa) has been approved for the treatment of advanced melanoma with some limited success. A class II IFN (IFN gamma), on the other hand, supports melanoma cell survival, possibly through constitutive activation of iNOS expression. We therefore conducted this study to explore the molecular pathways of MDA7/ IL-24 regulation of apoptosis via the intracellular induction of IFNs in melanoma. We hypothesized that the restoration of the MDA7/IL-24 axis leads to upregulation of Class I IFNs and induction of the apoptotic cascade. We found that MDA7/IL-24 induces the secretion of endogenous IFN beta, another class I IFN, leading to the arrest of melanoma cell growth and apoptosis. We also identified a series of apoptotic markers that play a role in this pathway, including the regulation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and Fas-FasL. In summary, we described a novel pathway of MDA7/IL-24 regulation of apoptosis in melanoma tumors via endogenous IFN beta induction followed by IRF regulation and TRAIL/FasL system activation.

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“…The anti-tumour effect of type I IFN in multiple myeloma as well as in ovarian cancer and cervical carcinoma cells is associated with upregulation of TRAIL. The importance of TRAIL in IFN-induced apoptosis is supported by the observation that inhibition of TRAIL-receptor DR5 activity appears to counteract the IFN antitumour effect [83,84,67]. Moreover, type I IFNs can sensitize tumor cells to TRAIL by regulating NF-kB activity and lenghtening S-phase progression [85,86,67].…”

Section: Apoptosis Inductionmentioning

confidence: 86%

“…The importance of TRAIL in IFN-induced apoptosis is supported by the observation that inhibition of TRAIL-receptor DR5 activity appears to counteract the IFN antitumour effect [83,84,67]. Moreover, type I IFNs can sensitize tumor cells to TRAIL by regulating NF-kB activity and lenghtening S-phase progression [85,86,67]. On the other hand, DNA microarray analysis has shown that TRAIL can induce the expression of several genes characteristic of the cellular response to IFN treatment, such as IRF-9/p48, STAT1, PKR, and IFI 6-16 as well as IFN- [87,88], showing the existence of a cross-talk between TRAIL and IFN signaling pathways.…”

Section: Apoptosis Inductionmentioning

confidence: 91%

“…Growth arrest appears to be mediated by c-myc downregulation and induction of p21 and p15 cyclin-dependent kinase inhibitors which leads to the accumulation of underphosphorylated pRB [62][63][64]. More recently, the study of a larger number of different cell types has evidenced that tumor cells typically respond to type I IFN with a strong accumulation in S phase, IFN-resulting more effective than IFN- [65][66][67][68][69][70][71][72]. Cell cycle arrest can be associated with cytostasis, cell size increase and apoptosis induction.…”

Section: Cell Cycle Regulationmentioning

confidence: 99%

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Perspectives in Biomolecular Therapeutic Intervention in Cancer: From the Early to the New Strategies With Type I Interferons

Vannucchi¹,

Chiantore

Mangino

et al. 2007

CMC

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Interferon (IFN) was the first cytokine produced by recombinant DNA technology used in wide-spread clinical treatment of infectious diseases as well as malignancies. The IFN clinical potential was clearly realized from the outset. However, IFN represents one of the most controversial drugs of our time, as remarkable cycles of promise and disappointment have affected its development and use. Considerable evidence regarding anti-tumor activities of IFNs has been reported. In this paper we focus on molecular bases of the IFN system that may relate to its antitumor activities. Many of the numerous genes transcriptionally activated by IFNs have been shown to encode proteins that activate immune recognition of tumor cells, directly or indirectly exert tumor suppressor activity and/or control tumor cell cycle and programmed cell death. In addition, a physiological relevant function for endogenous type I IFN in cancer immunoediting process and a new way to IFN clinical use based on gene therapy or vaccine-like approaches have recently been suggested. The identification of selected tissue-specific and/or tumor-specific target pathways as well as of different type I IFN tumor escape and resistance mechanisms may provide novel approaches in the search for new IFN-based therapeutic strategies to circumvent cancer disease or improve clinical outcome. Promising IFN treatment has been recently defined by using novel pharmaceutical preparations with a more favourable pharmacokinetic response, also in combination with other bioreagents or other modalities of therapy. Translational research, linking both basic and clinical research, will lead to a new rationale for the use of IFN in cancer therapy.

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TRAIL is a key target in S-phase slowing-dependent apoptosis induced by interferon-β in cervical carcinoma cells

Cited by 21 publications

References 37 publications

Type I Interferons Induce Apoptosis by Balancing cFLIP and Caspase-8 Independent of Death Ligands

Type I Interferons Induce Apoptosis by Balancing cFLIP and Caspase-8 Independent of Death Ligands

Killing of human melanoma cells induced by activation of class I interferon-regulated signaling pathways via MDA-7/IL-24

Perspectives in Biomolecular Therapeutic Intervention in Cancer: From the Early to the New Strategies With Type I Interferons

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