Targeting ErbB3 and Cellular NADPH/NADP⁺ Abundance Sensitizes Cutaneous Melanomas to Ferroptosis Inducers

Abstract

Melanoma is a serious health challenge. Ferroptosis is a regulated form of oxidative cell death that shows varied efficacy in melanoma. We aimed to better understand the molecular basis for this differential ferroptosis sensitivity. We find that elevated expression of ErbB3 (V-Erb-B2 Avian Erythroblastic Leukemia Viral Oncogene Homologue 3) associates with ferroptosis resistance and that ErbB3 knockdown sensitizes to ferroptosis inducers. ErbB3 depletion also promotes a marked reduction in the cellular ratio of GSH/GSSG (reduced/oxidized glutathione) and that of NADPH/NADP + (reduced/oxidized nicotinamide adenine dinucleotide phosphate), together with an increase in the abundance of the lipid peroxidation product malondialdehyde (MDA). We identify several small molecule inhibitors targeting ErbB3 signaling pathways that also reduce the NADPH/NADP + and GSH/GSSG ratios, concomitantly sensitizing the melanomas to ferroptosis activators. These findings point to a previously unrecognized role of ErbB3 in ferroptosis sensitivity and provide new insight into pathways that regulate this cell death process.

A Multifunctional Covalent Organic Framework Nanozyme for Promoting Ferroptotic Radiotherapy against Esophageal Cancer

“…Similarly, C11-BODIPY staining demonstrated that both the increase in X-ray absorption due to the presence of iodine and the LOX-mimicking activity of Fc promoted the accumulation of lipid peroxyl radicals, while Liperfluo staining illustrated that both contributed to lipid hydroperoxide accumulation (Figure C). A thiobarbituric acid colorimetric assay indicated that the level of malondialdehyde (MDA), the final product of lipid peroxidation, had increased consistently with radiotherapy, (Figure D) . Ellman’s method determined that intracellular GSH levels had been reduced following X-ray exposure due to the GPX-mimicking activity of Fc and radiotherapy-induced lipid peroxidation (Figure E).…”

“…A thiobarbituric acid colorimetric assay indicated that the level of malondialdehyde (MDA), the final product of lipid peroxidation, had increased consistently with radiotherapy, (Figure 7D). 102 Ellman's method determined that intracellular GSH levels had been reduced following X-ray exposure due to the GPX-mimicking activity of Fc and radiotherapy-induced lipid peroxidation (Figure 7E). Meanwhile, the activity of phospholipid hydroperoxidase (GPX4), the only enzyme that catalyzes the reduction of cytomembrane LPOs by GSH, also decreased with the GSH level, suggesting a breakdown of the oxidative defense system (Figure 7F).…”

Ferroptosis as a promising therapeutic strategy for melanoma

“…Aridanin exhibits antitumor activity by inducing ferroptosis ( Mbaveng et al, 2020 ). TX1-85-1, a small-molecule inhibitor targeting the ErbB3 signaling pathways, sensitizes melanomas to ferroptosis activators ( Leu et al, 2022 ). Mycalols trigger ferroptosis through downregulation of GPX4 and upregulation of NCOA4 ( Riccio et al, 2021 ).…”

Harnessing the Potential of Non-Apoptotic Cell Death Processes in the Treatment of Drug-Resistant Melanoma

“…Meanwhile, malondialdhyde (MDA) is the most significant end product of lipid peroxidation. By detecting MDA in cell lysates, the lipid peroxidation level can be determined [ 44 ]. Gagliardi et al also identified CHAC1 as an early ferroptotic marker in melanoma [ 35 ].…”

“…Cancer cells employ various mechanisms to escape cell death, including resistance to apoptosis and ferroptosis. For instance, melanoma cells have already been shown to develop resistance to ferroptosis [ 35 , 37 , 44 ]. Traditional therapies that target one single cell death pathway have accelerated the development of resistance; however, the development of therapeutic strategies that target multiple cell death pathways could circumvent the problem of drug resistance.…”