Erk1/2-Dependent HNSCC Cell Susceptibility to Erastin-Induced Ferroptosis

by Selleckchem | Jun 15 2023

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.

Comments:

The study aimed to investigate the vulnerability of head and neck squamous cell carcinoma (HNSCC) cells to ferroptosis induction, specifically focusing on the role of activated Erk1/2 and the druggable target xCT (SLC7A11).

The researchers observed that xCT (SLC7A11) was overexpressed in malignant tissues obtained from HNSCC patients, while normal mucosa demonstrated weak expression of the protein. This finding suggests that xCT may play a role in the progression of HNSCC.

To investigate the role of Erk1/2 activation in ferroptosis vulnerability, the researchers used HNSCC cells (FaDu and SCC25) that overexpressed xCT. They treated these cells with erastin, a compound known to induce ferroptosis. They found that inhibiting Erk1/2 signaling with ravoxertinib led to a decrease in erastin efficacy.

The decrease in erastin efficacy was attributed to several factors. First, inhibition of Erk1/2 signaling affected the production of reactive oxygen species (ROS), which are known to be involved in ferroptosis. Additionally, the researchers observed an upregulation of ROS scavengers, specifically SOD1 and SOD2, which reduced the levels of ROS and consequently repressed lipid peroxidation—an essential step in ferroptosis.

Based on these findings, the study concluded that the activation of ferroptosis through erastin represents a promising therapeutic approach that could be further developed for HNSCC treatment. Moreover, since the effectiveness of ferroptosis induction with erastin was dependent on the expression of Erk1/2, the researchers suggested that Erk1/2 could serve as a predictor for the response of HNSCC cells to erastin treatment.

These results highlight the potential of targeting the Erk1/2 signaling pathway and xCT (SLC7A11) as a strategy to overcome therapeutic resistance and improve outcomes in patients with HNSCC. Further research and clinical studies are needed to validate and expand upon these findings for potential clinical applications.