Abstract
BackgroundFerroptosis is an iron-dependent, lipid peroxide-mediated cell death that may be exploited to selective elimination of damaged and malignant cells. Recent studies have identified that small-molecule erastin specifically inhibits transmembrane cystine–glutamate antiporter system xc−, prevents extracellular cystine import and ultimately causes ferroptosis in certain cancer cells. In this study, we aimed to investigate the molecular mechanism underlying erastin-induced ferroptosis resistance in ovarian cancer cells.MethodsWe treated ovarian cancer cells with erastin and examined cell viability, cellular ROS and metabolites of the transsulfuration pathway. We also depleted cystathionine β-synthase (CBS) and NRF2 to investigate the CBS and NRF2 dependency in erastin-resistant cells.ResultsWe found that prolonged erastin treatment induced ferroptosis resistance. Upon exposure to erastin, cells gradually adapted to cystine deprivation via sustained activation of the reverse transsulfuration pathway, allowing the cells to bypass erastin insult. CBS, the biosynthetic enzyme for cysteine, was constantly upregulated and was critical for the resistance. Knockdown of CBS by RNAi in erastin-resistant cells caused ferroptotic cell death, while CBS overexpression conferred ferroptosis resistance. We determined that the antioxidant transcriptional factor, NRF2 was constitutively activated in erastin-resistant cells and NRF2 transcriptionally upregulated CBS. Genetically repression of NRF2 enhanced ferroptosis susceptibility.ConclusionsBased on these results, we concluded that constitutive activation of NRF2/CBS signalling confers erastin-induced ferroptosis resistance. This study demonstrates a new mechanism underlying ferroptosis resistance, and has implications for the therapeutic response to erastin-induced ferroptosis.
Highlights
Ferroptosis is an iron-dependent, lipid peroxide-mediated cell death that may be exploited to selective elimination of damaged and malignant cells
In an effort to investigate the effect of erastin in ferroptotic cell death in ovarian cancer cells, we found that erastin treatment could induce
Despite an initially sensitive chemotherapy, most ovarian cancers relapse with chemoresistance, which is featured by genotypic alteration and metabolic changes.[45,46,47]
Summary
Ferroptosis is an iron-dependent, lipid peroxide-mediated cell death that may be exploited to selective elimination of damaged and malignant cells. System xc− is a heterodimer composed of two distinct proteins: the substrate-specific subunit xCT known as SLC7A11 (solute carrier family 7), which is responsible for the transporter function of system xc−, and heavy chain of 4F2 cell surface antigen (4F2hc) SLC3A2 (solute carrier family 3 member 2).[6,7] Recent studies have identified that small-molecule erastin inhibits xCT, resulting in depletion of cellular GSH, and iron-dependent cell death, designated as ferroptosis.[8] Ferroptosis is featured by irresolvable lipid peroxidation, which is mechanistically triggered by ferrous iron (Fe2+)-mediated Fenton reaction.[9,10,11,12] Deprivation of cysteine by system xc− blockage leads to ferroptosis through
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