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Erk1/2-Dependent HNSCC Cell Susceptibility to Erastin-Induced Ferroptosis
Dragana Savic1,2, Teresa Bernadette Steinbichler3,4, Julia Ingruber3,4
1Laboratory for Experimental and Translational Research on Radiation Oncology (EXTRO-Lab), Department of Therapeutic Radiology and Oncology, Medical University of Innsbruck, A-6020 Innsbruck, Austria.
Abstract:
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.
Insights
Researchers found that activated Erk1/2 signaling in head and neck squamous cell carcinoma (HNSCC) cells increases vulnerability to ferroptosis. This suggests Erk1/2 could predict treatment response to erastin, a ferroptosis inducer.
Area of Science:
- Oncology
- Molecular Biology
- Cellular Mechanisms
Background:
- Head and neck squamous cell carcinoma (HNSCC) presents challenges due to therapeutic resistance and unfavorable clinical outcomes.
- Ferroptosis, a regulated cell death pathway, shows promise as a therapeutic strategy with druggable targets like xCT (SLC7A11).
- The specific mechanisms governing HNSCC cell susceptibility to ferroptosis remain largely unexplored.
Purpose of the Study:
- To investigate the role of activated Erk1/2 signaling in HNSCC cell sensitivity to ferroptosis induction.
- To determine if Erk1/2 activation influences the efficacy of ferroptosis-inducing agents like erastin.
Main Methods:
- Analysis of xCT (SLC7A11) expression in HNSCC tissues versus normal mucosa.
- Utilizing xCT-overexpressing FaDu and SCC25 HNSCC cell lines to study the impact of Erk1/2 inhibition on erastin efficacy.
- Assessing the effects of ravoxertinib-mediated Erk1/2 inhibition on reactive oxygen species (ROS) production, ROS scavengers (SOD1, SOD2), and lipid peroxidation.
Main Results:
- xCT (SLC7A11) was significantly overexpressed in malignant HNSCC tissues compared to normal mucosa.
- Inhibition of Erk1/2 signaling by ravoxertinib reduced the efficacy of erastin.
- This reduction in efficacy was linked to decreased ROS production, upregulation of SOD1 and SOD2, and suppressed lipid peroxidation.
Conclusions:
- Erastin-induced ferroptosis is a potential therapeutic strategy for HNSCC.
- Activated Erk1/2 signaling in HNSCC cells enhances their vulnerability to ferroptosis.
- Erk1/2 can serve as a predictive biomarker for HNSCC response to erastin-based therapies.
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