Oncotarget

Research Papers:

This article has been corrected. Correction in: Oncotarget. 2023; 14:782-787.

Interferon beta induces apoptosis in nasopharyngeal carcinoma cells via the TRAIL-signaling pathway

Anna Makowska, Lora Wahab, Till Braunschweig, Nikiforos-Ioannis Kapetanakis, Christian Vokuhl, Bernd Denecke, Lian Shen, Pierre Busson and Udo Kontny _

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Oncotarget. 2018; 9:14228-14250. https://doi.org/10.18632/oncotarget.24479

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Abstract

Anna Makowska1, Lora Wahab1, Till Braunschweig2, Nikiforos-Ioannis Kapetanakis3, Christian Vokuhl4, Bernd Denecke5, Lian Shen1, Pierre Busson3 and Udo Kontny1

1Division of Pediatric Hematology, Oncology and Stem Cell Transplantation, Medical Faculty, RWTH Aachen University, Aachen, Germany

2Institute of Pathology, Medical Faculty, RWTH Aachen University, Aachen, Germany

3CNRS UMR 8126, Gustave Roussy and Université Paris-Sud/Paris-Saclay, Villejuif, France

4Institute of Pathology, Kiel Pediatric Tumor Registry, Christian-Albrechts-University, Kiel, Germany

5IZKF, Medical Faculty, RWTH Aachen University, Aachen, Germany

Correspondence to:

Udo Kontny, email: [email protected]

Keywords: nasopharyngeal carcinoma; interferon beta; TRAIL; apoptosis; siRNA

Received: June 08, 2017     Accepted: February 02, 2018     Epub: February 12, 2018     Published: March 06, 2018

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.


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