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Targeting ferroptosis in gefitinib-resistant HCC827 NSCLC cells using erastin
A-Young Nam1, Sang Hoon Joo2, Na Yeong Lee1
1Department of Biomedicine, Health and Life Convergence Sciences, BK21 Four, College of Pharmacy, Mokpo National University Muan 58554, Republic of Korea.
Abstract:
Overcoming drug resistance remains essential for improving clinical outcomes in non-small cell lung cancer (NSCLC). This study explores the differential susceptibility of drug-resistant cancer cells, utilizing gefitinib (GEF)-resistant HCC827GR NSCLC cells as a model system. We observed that HCC827GR cells inherently display elevated levels of reactive oxygen species (ROS) and increased expression of ferroptosis-related markers when compared with GEF-sensitive cells. Accordingly, the HCC827GR lineage showed heightened responsiveness to erastin-mediated cytotoxicity, as determined by MTT and soft-agar assays. Our mechanistic investigations established that erastin treatment resulted in non-apoptotic cell death, accompanied by mitochondrial dysfunction and G2/M phase arrest in the cell cycle. In-depth analysis demonstrated that erastin notably raised intracellular iron and ROS concentrations and induced lipid peroxidation. Pretreatment with N-acetyl cysteine (NAC) validated the crucial involvement of ROS, and the use of ferrostatin-1 conclusively verified ferroptosis as the predominant mode of cell death. In summary, GEF-resistant HCC827GR cells exhibit increased sensitivity to erastin-induced ferroptosis compared with the parental line. This distinct vulnerability should be further studied as a potential therapeutic approach for targeting drug-resistant NSCLC.
Insights
Drug-resistant non-small cell lung cancer (NSCLC) cells show increased sensitivity to erastin-induced ferroptosis. This vulnerability in gefitinib-resistant cells presents a potential therapeutic strategy for overcoming treatment resistance.
Area of Science:
- Oncology
- Cell Biology
- Drug Resistance
Background:
- Drug resistance is a major challenge in non-small cell lung cancer (NSCLC) treatment.
- Gefitinib (GEF)-resistant HCC827GR cells were used to model acquired resistance.
- Understanding differential cell susceptibility is crucial for novel therapeutic strategies.
Purpose of the Study:
- To investigate the susceptibility of drug-resistant NSCLC cells to ferroptosis.
- To explore the underlying mechanisms of erastin-induced cell death in resistant cells.
- To evaluate ferroptosis as a potential therapeutic vulnerability in drug-resistant NSCLC.
Main Methods:
- Utilized gefitinib-resistant HCC827GR NSCLC cells and parental gefitinib-sensitive cells.
- Assessed erastin-induced cytotoxicity using MTT and soft-agar assays.
- Investigated cell death mechanisms, mitochondrial function, cell cycle, intracellular iron, reactive oxygen species (ROS), and lipid peroxidation.
- Employed N-acetyl cysteine (NAC) and ferrostatin-1 to confirm ROS involvement and ferroptosis.
Main Results:
- HCC827GR cells exhibited higher intrinsic reactive oxygen species (ROS) and ferroptosis markers.
- GEF-resistant cells showed heightened sensitivity to erastin-mediated cytotoxicity.
- Erastin induced non-apoptotic cell death, mitochondrial dysfunction, and G2/M cell cycle arrest.
- Erastin increased intracellular iron, ROS, and lipid peroxidation; NAC and ferrostatin-1 confirmed ferroptosis.
Conclusions:
- Gefitinib-resistant HCC827GR cells are more sensitive to erastin-induced ferroptosis than parental cells.
- Erastin triggers ferroptosis through increased intracellular iron, ROS, and lipid peroxidation.
- This heightened sensitivity to ferroptosis represents a potential therapeutic avenue for drug-resistant NSCLC.
