title: Inhibition of SphK1 reduces radiation-induced migration and enhances sensitivity to cetuximab treatment by affecting the EGFR / SphK1 crosstalk.
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.
authors.affiliation: Department of Otolaryngology Head and Neck Surgery, Technical University of Munich, 81675 Muenchen, Germany.
authors.forename: Carlotta
authors.initials: C
authors.lastname: Schiefler
authors.affiliation: Department of Otolaryngology Head and Neck Surgery, Technical University of Munich, 81675 Muenchen, Germany.
authors.forename: Guido
authors.initials: G
authors.lastname: Piontek
authors.affiliation: Department of Otolaryngology Head and Neck Surgery, Technical University of Munich, 81675 Muenchen, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Doescher
authors.affiliation: Department of Otolaryngology Head and Neck Surgery, Technical University of Munich, 81675 Muenchen, Germany.
authors.forename: Dominik
authors.initials: D
authors.lastname: Schuettler
authors.affiliation: Department of Radiotherapy, Technical University of Munich, 81675 Muenchen, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Mißlbeck
authors.affiliation: Institute of Pathology, Julius-Maximilians-University and Comprehensive Cancer Center Mainfranken, Josef-Schneider-Straße 2, 97080 Wuerzburg, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Rudelius
authors.affiliation: Department of Otolaryngology, University of Innsbruck, Anichstr. 35, 6020 Innsbruck, Austria.
authors.forename: Anna
authors.initials: A
authors.lastname: Haug
authors.affiliation: Department of Otolaryngology Head and Neck Surgery, Section of Phoniatrics and Pedaudiology, University of Ulm, Prittwitzstr. 43, 89075 Ulm, Germany.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Reiter
authors.affiliation: Department of Gynecology and Obstetrics, University of Regensburg, 93053 Regensburg, Germany.
authors.forename: Gero
authors.initials: G
authors.lastname: Brockhoff
authors.affiliation: Department of Otolaryngology Head and Neck Surgery, Technical University of Munich, 81675 Muenchen, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Pickhard
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000201:enzymology / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D000068818:Cetuximab; D018450:Disease Progression; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000532:radiotherapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D016612:Paraffin Embedding; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020239:Receptor Cross-Talk / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects; D000077195:Squamous Cell Carcinoma of Head and Neck; D013844:Thiazoles / Q000494:pharmacology; D000099157:Sphingosine Kinase
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000068818:Cetuximab; D066246:ErbB Receptors; D017853:Phosphotransferases (Alcohol Group Acceptor); D013844:Thiazoles; D000099157:Sphingosine Kinase; C525025:4-(4-(4-chloro-phenyl)thiazol-2-ylamino)phenol; C512478:EGFR protein, human