Inhibition of SphK1 reduces radiation-induced migration and enhances sensitivity to cetuximab treatment by affecting the EGFR / SphK1 crosstalk

Carlotta Schiefler; Guido Piontek; Johannes Doescher; Dominik Schuettler; Martin Mißlbeck; Martina Rudelius; Anna Haug; Rudolf Reiter; Gero Brockhoff; Anja Pickhard

doi:10.18632/oncotarget.2436

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Research Papers:

Inhibition of SphK1 reduces radiation-induced migration and enhances sensitivity to cetuximab treatment by affecting the EGFR / SphK1 crosstalk

Carlotta Schiefler _, Guido Piontek, Johannes Doescher, Dominik Schuettler, Martin Mißlbeck, Martina Rudelius, Anna Haug, Rudolf Reiter, Gero Brockhoff and Anja Pickhard

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Oncotarget. 2014; 5:9877-9888. https://doi.org/10.18632/oncotarget.2436

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Abstract

Carlotta Schiefler1, Guido Piontek1, Johannes Doescher1, Dominik Schuettler1, Martin Mißlbeck2, Martina Rudelius3, Anna Haug4, Rudolf Reiter5, Gero Brockhoff6, Anja Pickhard1

1Department of Otolaryngology Head and Neck Surgery, Technical University of Munich, Ismaninger Str. 22, 81675 Muenchen, Germany

2Department of Radiotherapy, Technical University of Munich, Ismaninger Str. 22, 81675 Muenchen, Germany

3Institute of Pathology, Julius-Maximilians-University and Comprehensive Cancer Center Mainfranken, Josef-Schneider-Straße 2, 97080 Wuerzburg, Germany

4Department of Otolaryngology, University of Innsbruck, Anichstr. 35, 6020 Innsbruck, Austria

5Department of Otolaryngology Head and Neck Surgery, Section of Phoniatrics and Pedaudiology, University of Ulm, Prittwitzstr. 43, 89075 Ulm, Germany

6Department of Gynecology and Obstetrics; University of Regensburg, Landshuter Str. 65, 93053 Regensburg, Germany

Correspondence to:

Dr. Anja Pickhard, e-mail: [email protected]

Keywords: SphK1, EGFR, HNSCC, radiation, radiation-induced migration

Received: April 30, 2014 Accepted: September 05, 2014 Published: September 10, 2014

ABSTRACT

SphK1 is known to play a role in tumor progression, resistance to radiochemotherapy, and migration patterns. As the overall survival rates of squamous cell carcinoma of the head and neck (HNSCC) remain poor due to limitations in surgery and irradiation and chemotherapy resistance, SphK1 is an important enzyme to investigate. The purpose of this study was to elucidate the impact of SphK1 on irradiation efficacy of HNSCC in-vitro with emphasis on EGFR signaling. By immunhistochemical staining we found a positive correlation between EGFR and SphK1 expression in patient specimens. In colony formation assays irradiation sensitive cell lines showed a poor response to cetuximab, an EGFR inhibitor, and SKI-II, a SphK1 inhibitor, and vice versa. In irradiation sensitive cells an enhanced reduction of cell migration and survival was found upon simultaneous targeting of EGFR and SphK1. In the present study, we elucidated a linkage between the two signaling pathways with regard to the efficacy of cetuximab treatment and the impact on the migration behavior of tumor cells. We investigated the biological impact of inhibiting these pathways and examined the biochemical implications after different treatments. An understanding of the processes involved could help to improve the treatment of patients with HNSCC.

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Research Papers:

Inhibition of SphK1 reduces radiation-induced migration and enhances sensitivity to cetuximab treatment by affecting the EGFR / SphK1 crosstalk

Abstract