Erk1/2-Dependent HNSCC Cell Susceptibility to Erastin-Induced Ferroptosis
Dragana Savic,
Teresa Bernadette Steinbichler,
Julia Ingruber,
Giulia Negro,
Bertram Aschenbrenner,
Herbert Riechelmann,
Ute Ganswindt,
Sergej Skvortsov,
József Dudás,
Ira-Ida Skvortsova
Affiliations
Dragana Savic
Laboratory for Experimental and Translational Research on Radiation Oncology (EXTRO-Lab), Department of Therapeutic Radiology and Oncology, Medical University of Innsbruck, A-6020 Innsbruck, Austria
Teresa Bernadette Steinbichler
Department of Otorhinolaryngology and Head and Neck Surgery, Medical University of Innsbruck, A-6020 Innsbruck, Austria
Julia Ingruber
Department of Otorhinolaryngology and Head and Neck Surgery, Medical University of Innsbruck, A-6020 Innsbruck, Austria
Giulia Negro
Laboratory for Experimental and Translational Research on Radiation Oncology (EXTRO-Lab), Department of Therapeutic Radiology and Oncology, Medical University of Innsbruck, A-6020 Innsbruck, Austria
Bertram Aschenbrenner
Department of Dermatology, Medical University of Vienna, A-1090 Vienna, Austria
Herbert Riechelmann
Department of Otorhinolaryngology and Head and Neck Surgery, Medical University of Innsbruck, A-6020 Innsbruck, Austria
Ute Ganswindt
Department of Therapeutic Radiology and Oncology, A-6020 Innsbruck, Austria
Sergej Skvortsov
Laboratory for Experimental and Translational Research on Radiation Oncology (EXTRO-Lab), Department of Therapeutic Radiology and Oncology, Medical University of Innsbruck, A-6020 Innsbruck, Austria
József Dudás
Department of Otorhinolaryngology and Head and Neck Surgery, Medical University of Innsbruck, A-6020 Innsbruck, Austria
Ira-Ida Skvortsova
Laboratory for Experimental and Translational Research on Radiation Oncology (EXTRO-Lab), Department of Therapeutic Radiology and Oncology, Medical University of Innsbruck, A-6020 Innsbruck, Austria
Unfavorable clinical outcomes mean that cancer researchers must attempt to develop novel therapeutic strategies to overcome therapeutic resistance in patients with HNSCC. Recently, ferroptosis was shown to be a promising pathway possessing druggable targets, such as xCT (SLC7A11). Unfortunately, little is known about the molecular mechanisms underlying the susceptibility of HNSCC cells to ferroptosis. The goal of this study was to determine whether HNSCC cells with activated Erk1/2 are vulnerable to ferroptosis induction. Our results have shown that xCT (SLC7A11) was overexpressed in malignant tissues obtained from the patients with HNSCC, whereas normal mucosa demonstrated weak expression of the protein. In order to investigate the role of Erk1/2 in the decrease in cell viability caused by erastin, xCT-overexpressing FaDu and SCC25 HNSCC cells were used. The ravoxertinib-dependent inhibition of Erk1/2 signaling led to the decrease in erastin efficacy due to the effect on ROS production and the upregulation of ROS scavengers SOD1 and SOD2, resulting in repressed lipid peroxidation. Therefore, it was concluded that the erastin-dependent activation of ferroptosis seems to be a promising approach which can be further developed as an additional strategy for the treatment of HNSCC. As ferroptosis induction via erastin is strongly dependent on the expression of Erk1/2, this MAP kinase can be considered as a predictor for cancer cells’ response to erastin.
