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Erastin induces apoptotic and ferroptotic cell death by inducing ROS accumulation by causing mitochondrial
Yingwei Sun1, Rongrong Deng2, Cuiwei Zhang3
1Department of Pharmacy, The Teaching Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 610072, P.R. China.
Abstract:
Erastin, a classical inducer of non‑apoptotic cell death, exerts cytotoxicity in several types of cancer cells, including gastric cancer cells, by depleting glutathione, which is a primary cellular antioxidant, thus causing reactive oxygen species (ROS) accumulation. Although numerous studies have focused on the non‑apoptotic cell death induced by erastin, whether erastin induces apoptosis remains unknown. The present study confirmed the cytotoxicity of erastin in HGC‑27 cells and used a 30% inhibitory concentration (IC30, approximately 6.23 µM) for further analysis. The cell cycle analysis revealed that 6.23 µM of erastin inhibited proliferation by blocking the cell cycle at the G1/G0 phase. Further analysis also showed that 6.23 µM of erastin clearly inhibited HGC‑27 malignant behaviors, including migration, invasion, colony formation and tumor formation in soft agar. The observation of ROS accumulation due to erastin treatment led to determination of the effects of erastin on mitochondrial function and, as expected, erastin treatment decreased transcriptional activity and ATP production in mitochondria and disrupted the mitochondrial potential; these effects were reversed by the addition of the ROS scavenger NAC. To evaluate the effect of erastin in inducing apoptosis, HGC‑27 cells were treated with 6.23 µM of erastin for 7 days and then analyzed. Evident apoptotic cell death was induced by erastin and this apoptosis was reversed by the addition of an apoptosis inhibitor (zVAD) or NAC but not by the addition of a ferroptosis inhibitor (ferrostatin‑1). Furthermore, the detection of caspase‑3 and poly (adenosine diphosphate‑ribose) polymerase (PARP) also confirmed that treatment with erastin promoted the cleavage of caspase‑3 and PARP, which are hallmarks of apoptosis. Taken together, the present study revealed that a low dose of erastin inhibited malignant behavior and induced apoptosis by causing mitochondrial dysfunction.
Insights
Erastin, a compound that induces non-apoptotic cell death, also triggers apoptosis in gastric cancer cells by disrupting mitochondrial function and increasing reactive oxygen species (ROS). This study reveals erastin
Area of Science:
- Cell Biology
- Cancer Research
- Biochemistry
Background:
- Erastin is known to induce non-apoptotic cell death by depleting glutathione and increasing reactive oxygen species (ROS).
- The potential of erastin to induce apoptosis, a programmed cell death pathway, remained largely unexplored.
- Gastric cancer cells (HGC-27) were used to investigate erastin's effects.
Purpose of the Study:
- To determine if erastin induces apoptosis in gastric cancer cells.
- To elucidate the mechanisms underlying erastin's cytotoxicity, including its effects on cell cycle, malignant behaviors, and mitochondrial function.
- To investigate the role of ROS and mitochondrial dysfunction in erastin-induced cell death.
Main Methods:
- HGC-27 cells were treated with erastin at its IC30 concentration (6.23 µM).
- Cell cycle analysis, migration, invasion, colony formation, and soft agar assays were performed.
- Mitochondrial function, ROS levels, and apoptosis markers (caspase-3, PARP cleavage) were assessed.
- Experiments included treatments with ROS scavenger (NAC), apoptosis inhibitor (zVAD), and ferroptosis inhibitor (ferrostatin-1).
Main Results:
- Erastin inhibited HGC-27 cell proliferation by causing G1/G0 cell cycle arrest.
- Erastin suppressed HGC-27 cell migration, invasion, colony formation, and anchorage-independent growth.
- Erastin induced ROS accumulation, impaired mitochondrial function (decreased ATP production, disrupted potential), and triggered apoptotic cell death.
- Apoptosis induction was confirmed by caspase-3 and PARP cleavage and was reversible by NAC and zVAD, but not ferrostatin-1.
Conclusions:
- Low-dose erastin inhibits gastric cancer cell proliferation and malignant behaviors.
- Erastin induces apoptosis in HGC-27 cells through mitochondrial dysfunction and ROS generation.
- These findings reveal a dual role for erastin in cancer cell death, involving both non-apoptotic and apoptotic pathways.
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