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Dual effects of erastin on aggressive osteosarcoma cells: ferroptosis sensitization and anti-ferroptotic gene
Gordon Daniel Burns1, Kevin Schneider1, Shari Atilano1
1Department of Ophthalmology, Gavin Herbert Eye Institute, University of California Irvine, Irvine, CA 92697 USA.
Abstract:
Osteosarcoma (OS) is a rare cancer, yet the most prevalent primary bone cancer in adolescents and young adults OS can be fatal and detrimental due to its high aggressiveness, early metastases, and chemo-resistance. Recent research suggests that drugs that induce ferroptosis could treat osteosarcoma. It is unknown how erastin-induced ferroptosis influences differential gene expression of System Xc, iron absorption, heme synthesis, and mono- (MUFA) and polyunsaturated (PUFA) fatty acid levels in aggressive OS cells. In this study, we show that erastin-induced ferroptosis decreases OS cell growth and survival by raising total ROS, mitochondrial membrane potential, and downregulating VDAC2. Furthermore, erastin induces elevated levels of SLC7A11 and SLC3A2, but downregulation of TFRC and HMOX1 in OS cells. Notably, the addition of Ferrostatin-1 protects against Erastin-induced cytotoxicity, implying that these agents induce ferroptosis. We also showed that Ferrostatin-1 provides partial protection against Erastin-induced ferroptosis by stimulating the unique transcriptional gene profile of System Xc-, MUFA, and PUFA while inhibiting iron uptake and heme production in OS cells. These findings show that Erastin inhibits the survival of aggressive OS cells, but it also increases the expression of genes linked with anti-ferroptosis activity, which could lead to preventing ferroptosis in the aggressive OS phenotype. Targeting this anti-ferroptotic differential gene expression mediated by erastin-induced ferroptosis in OS cells may help to improve erastin's efficacy.
Supplementary Information:
The online version contains supplementary material available at 10.1007/s10616-025-00795-7.
Insights
Erastin induces ferroptosis in osteosarcoma cells, decreasing their growth and survival. However, it also upregulates anti-ferroptosis genes, potentially limiting treatment efficacy. Targeting these genes may improve erastin therapy for osteosarcoma.
Area of Science:
- Oncology
- Cell Biology
- Biochemistry
Background:
- Osteosarcoma (OS) is an aggressive bone cancer common in young adults, characterized by poor outcomes due to early metastasis and chemo-resistance.
- Emerging research indicates that inducing ferroptosis, a form of programmed cell death, may offer a novel therapeutic strategy for osteosarcoma.
- The specific impact of erastin-induced ferroptosis on gene expression related to System Xc, iron metabolism, and fatty acid profiles in aggressive OS cells remains largely unexplored.
Purpose of the Study:
- To investigate the effects of erastin on ferroptosis induction in aggressive osteosarcoma (OS) cells.
- To analyze the differential gene expression patterns influenced by erastin, focusing on System Xc, iron absorption, heme synthesis, and fatty acid levels.
- To assess the potential of targeting anti-ferroptotic gene expression to enhance erastin's therapeutic efficacy in OS.
Main Methods:
- Treatment of aggressive OS cells with erastin to induce ferroptosis.
- Measurement of reactive oxygen species (ROS) and mitochondrial membrane potential.
- Analysis of gene expression for key markers including VDAC2, SLC7A11, SLC3A2, TFRC, and HMOX1.
- Assessment of erastin's effects with and without Ferrostatin-1, a ferroptosis inhibitor.
Main Results:
- Erastin significantly decreased OS cell growth and survival by increasing ROS and mitochondrial membrane potential, and downregulating VDAC2.
- Erastin elevated the expression of SLC7A11 and SLC3A2 while downregulating TFRC and HMOX1.
- Ferrostatin-1 partially protected against erastin-induced ferroptosis, confirming erastin's mechanism and highlighting the upregulation of anti-ferroptosis genes.
Conclusions:
- Erastin effectively induces ferroptosis in aggressive osteosarcoma cells, leading to reduced cell viability.
- Erastin treatment paradoxically upregulates genes associated with anti-ferroptosis, potentially conferring resistance.
- Targeting this erastin-mediated upregulation of anti-ferroptosis genes presents a promising strategy to improve the efficacy of ferroptosis-inducing drugs for osteosarcoma treatment.
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