Type I interferon and TNFα cooperate with type II interferon for TRAIL induction and triggering of apoptosis in SK-N-MC EWING tumor cells

Abstract

Ewing's sarcoma is the second most common human bone tumor in childhood. Here, we investigated the sensitivity of the Ewing tumor cell line, SK-N-MC, to the apoptotic effect of type I (IFNa) and type II (IFNc) interferons and TNFa. We demonstrate that although IFNa and TNFa alone are unable to induce cell death, they act in synergy with IFNc to induce SK-N-MC cell apoptosis. The synergistic induction of apoptosis correlated with the synergistic induction of TNFa-related apoptosis-inducing ligand (TRAIL) mRNA and TRAIL protein synthesis as well as of TRAIL secretion. Preparations of inducer-free supernatants from SK-N-MC cells stimulated with combinations of cytokines were shown to be cytotoxic for untreated SK-N-MC cells. This cytotoxicity was partially inhibited by addition of TRAILR2/Fc fusion protein, indicating that the secreted TRAIL mediates, at least in part, the apoptotic effect displayed by the supernatants of stimulated SK-N-MC cells. We have shown that the presence of IFNc is required to allow the sustained expression of IRF1 in SK-N-MC cells stimulated by addition of IFNa or TNFa suggesting that IRF1 plays a role in the synergistic induction of apoptosis by combinations of cytokines. Furthermore, we have shown that inhibition of NF-jB activation contributes to the IFNc-mediated sensitization to the apoptotic effect of TNFa. To our knowledge, this is the first report showing that interferon/cytokine combinations are able to induce TRAIL gene expression and TRAIL protein synthesis and secretion in Ewing sarcoma-derived cells. We believe that the observations reported here might contribute to the development of alternative new approaches to the treatment of Ewing tumors resistant to conventional therapy.

Fas/Fas ligand regulation mediates cell death in human Ewing's sarcoma cells treated with melatonin

“…The increased expression of a death receptor ligand, either alone or accompanied by the increase in its receptor, has been previously shown to induce cell death in Ewing's sarcoma cells. Abadie et al (2004) reported that a combination of cytokines (TNF- α with interferon γ or interferon α with interferon γ ) induces cell death in SK-N-MC cells, and that this is mediated by the increased expression of TRAIL. A collaboration of TRAIL and interferon γ was also observed in vivo in a xenograft model of Ewing's sarcoma (Merchant et al , 2004).…”

Mast cells dysregulate apoptotic and cell cycle genes in mucosal squamous cell carcinoma

“…Up-regulation of TRAIL gene expression and protein synthesis is known to occur in Ewing sarcoma, and thyroid carcinoma cell lines following intereferon (IFN)/cytokine treatment, contributing to apoptosis of the malignant cells in an autocrine and paracrine manner [10,11]. TRAIL serum levels in melanoma patients are found to be significantly elevated following IFN-α administration [12].…”

Pharmacological management of Ewing sarcoma family of tumours

“…However, further investigation of this pathway is underway. It has been shown that IFNs can induce expression of TRAIL [99], and recent studies have documented strong synergistic in vitro and in vivo antitumour effects when Type I IFN-α or -β are given with ifosfamide [100] or with Type II IFN-γ [101]. Furthermore, in these preclinical models, the antitumour effect correlates with TRAIL induction, which would suggest that TRAIL contributes to the triggering of apoptosis in ESFT cells in an autocrine or paracrine manner.…”