Erastin decreases radioresistance of NSCLC cells partially by inducing GPX4‑mediated ferroptosis

Abstract

The aim of the present study was to examine whether erastin influences radioresistance in non-small cell lung cancer (NSCLC) cells and produce a preliminary investigation into its mechanism of action. The radioresistant subtype of NSCLC cells, A549-R and H460-R, were induced by high-dose hypofractionated irradiation. Erastin was used to treat the radioresistant cells and radiosensitivity was examined by colony formation assays. Cell death was determined after the cells were treated with erastin, irradiation (IR) or erastin together with IR. The expression of glutathione peroxidase 4 (GPX4) expression in the parental cells and radioresistance cells was detected by western blotting. GPX4 expression in the radioresistance cells was subsequently inhibited, radiosensitivity and cell death was measured, and erastin enhanced radiosensitivity in A549-R and H460-R cells. Erastin and IR exhibited a combined effect on killing cells, as co-treatment with erastin and IR demonstrated a higher effect on killing cells compared with erastin or IR alone. GPX4 expression was inhibited by erastin in the radioresistant cells. Inhibiting GPX4 expression also radiosensitized NSCLC cells to radiation in the radioresistant cell lines. Erastin-induced and GPX4-inhibition-induced cell death could partially be rescued by deferoxamine, but not Z-VAD-FMK and olaparib, which indicated that erastin and GPX4-inhibition induced ferroptosis in the radioresistant cells. Erastin decreased radioresistance of NSCLC cells partially by inducing GPX4-mediated ferroptosis.

The Intersection of DNA Damage Response and Ferroptosis—A Rationale for Combination Therapeutics

“…Thus, the intersection between ferroptosis and DDR suggests that inducing ferroptosis may overcome radioresistance and improve the response ( Figure 2 ). This concept has been supported by several studies that have shown synergistic effects between IR and ferroptosis in various tumor models mentioned previously [ 72 , 73 , 75 , 76 ]. As an extension of this concept, it is possible that other cancer therapeutics that trigger DNA damage responses, such as PARP inhibitors or cisplatin, may synergize with ferroptosis-inducing agents for maximal clinical benefits.…”

“…Since IR induces DNA damage and activates ATM [ 71 ], it is reasonable to speculate that IR therapy may enhance ferroptosis. Indeed, the Yu and Chen groups showed that IR could further sensitize the ferroptosis of nonsmall cell lung carcinoma (NSCLC) in a GPX4-dependent manner [ 72 ]. In another study, Shibata and colleagues also demonstrated the synergistic antitumor effect of erastin and X-ray irradiation through the delayed growth of xenograft models [ 73 ].…”

Ferroptosis in Cancer Treatment: Another Way to Rome

“…GPX4 expression is increased in radioresistant NSCLC cells, and knocking down GPX4 or using ferroptosis inducers that target GPX4 can enhance the sensitivity of radiation-resistant lung cancer cells after high-dose hypofractionated irradiation. Erastin and IR exhibited a combined cell killing effect compared with either erastin or IR alone ( 84 ). Moreover, co-treatment with oxyfedrine (OXY) can trigger the intracellular accumulation of lipid peroxidation and enhance cell death ( 82 ).…”

Frizzled-7 Identifies Platinum Tolerant Ovarian Cancer Cells Susceptible to Ferroptosis

“…Given the direct correlations observed between FZD7, upregulated in platinum-tolerant cells, and GPX4-mediated cellular redox maintenance, we hypothesized that inhibition of this axis could eliminate resistant cancer cells. Small molecule inhibitors of GPX4 have been shown to increase cellular oxidative stress and to induce ferroptosis, an iron-dependent lipid peroxide-induced cell death (2,(31)(32)(33). Thus, we examined the sensitivity of OC cells with high vs. low FZD7 expression levels to GPX4 inhibitors, ML210 and RSL3 (2,33,34).…”