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

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.

NADPH Oxidase Subunit CYBB Confers Chemotherapy and Ferroptosis Resistance in Mesenchymal Glioblastoma via Nrf2/SOD2 Modulation

“…The results of this study corroborate the previous reports that have highlighted the importance of SOD2 in buffering superoxide accumulation, as well as dictating sensitivity to chemotherapy and pro-ferroptosis agents [7,25,26]. Specifically, our study showed that the depletion of SOD2 in TMZ-resistant GBM cells re-sensitized them to erastin-mediated ferroptosis, both in vitro and in vivo.…”

“…It has been known that the major form of ROS produced within mitochondria is superoxide [8]. Previous studies have shown that decreased cellular antioxidant capacity, such as SOD2 levels, contributes to ferroptosis [26,27]. The antioxidative function of SOD2 is located within the mitochondrial matrix, where it converts superoxide anions produced by mitochondria during electron transport chain (ETC) to a less harmful radical, hydrogen peroxide (H 2 O 2 ).…”

“…On the other hand, SOD2 deficiency leads to superoxide accumulation in the mitochondria, leading to oxidative stress. As both erastin and TMZ treatment produce ROS in cells [13,26], a depletion of SOD2 in the mitochondria can further increase superoxide levels. A higher superoxide level leads to increased lipid peroxidation in membranes and the occurrence of ferroptosis [28].…”