Abstract
The combination of neoadjuvant chemotherapy, radiochemotherapy, and maintenance therapy with interferon beta (IFNβ) has led to superior results in the treatment of children and adolescents with nasopharyngeal carcinoma (NPC). However, nothing is known about the mechanism of the antitumor activity of IFNβ in NPC. Here, we investigate the role of IFNβ on apoptosis in NPC cells. Six NPC cell lines, one patient-derived NPC xenograft (PDX) and one SV40-transformed nasoepithelial cell line were used. Induction of apoptosis by IFNβ was measured by flow cytometric analysis of subG1-DNA-content, Hoechst 33258 staining and activation of caspase-3. Dissection of death ligand signaling pathways included measuring surface expression of its components by flow cytometry, activation by death ligands and neutralization with specific antibodies and siRNA. IFNβ induced apoptosis at concentrations achievable in humans in five of six NPC cell lines and in PDX cells but not in nasoepithelial cells. Inhibition of caspases-3 and −8 abrogated this effect suggesting IFNβ promoted apoptosis through the extrinsic pathway. IFNβ induced surface expression of TRAIL and TRAIL-R2 and the addition of an anti-TRAIL-antibody or transfection with TRAIL-siRNA blocked IFNβ-induced apoptosis. No induction of TRAIL-expression was noted in the IFNβ-resistant cell line. In conclusion, IFNβ leads to apoptosis in NPC cells in an autocrine way via the induction of TRAIL expression and subsequent activation of the TRAIL-signaling pathway. The mechanism described could at least partly explain the clinical benefit of IFNβ in the treatment of NPC. Further studies in a mouse-xenograft model are warranted to substantiate this effect in vivo.
Highlights
Nasopharyngeal carcinoma (NPC) is a malignant tumor arising from the surface epithelium of the posterior nasopharynx
Since we showed that IFNβ induced apoptosis in nasopharyngeal carcinoma (NPC) cells via the extrinsic apoptotic pathway and that the Tumor Necrosis Factor-Related Apoptosis Inducing Ligand (TRAIL)-signaling pathway was intact in these cells, we wondered whether IFNβ induced expression of TRAIL in NPC cells
In this study we have shown that IFNβ induces apoptosis in the majority of NPC cell lines and in cells of a patient-derived xenograft at concentrations achievable in humans and that the mechanism of induction of apoptosis is based on the expression of TRAIL in NPC cells and subsequent activation of the TRAIL-signaling pathway in an autocrine way
Summary
Nasopharyngeal carcinoma (NPC) is a malignant tumor arising from the surface epithelium of the posterior nasopharynx. Most cases of NPC in children, adolescents and young adults present as advanced locoregional disease [3,4,5,6,7]. Survival www.impactjournals.com/oncotarget chances for children with locoregional disease range between 80% and 90% and failures are mostly due to the development of distant relapses. Whereas simultaneous radiochemotherapy has been considered as standard therapy for adults with nasopharyngeal carcinoma [8], in children and adolescents, the addition of neoadjuvant chemotherapy has led to superior results [4,5,6,7]. The GPOH concept is unique by the fact that in addition to neoadjuvant chemotherapy followed by radiochemotherapy, maintenance therapy with interferon-β (IFNβ) is given for 6 months [9]. No biological studies have so far been conducted, exploring the effect of IFNβ in NPC cells
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