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SBFI26 induces triple-negative breast cancer cells ferroptosis via lipid peroxidation
Gang He1, Yiyuan Zhang1, Yanjiao Feng1
1Key Laboratory of Medicinal and Edible Plants Resources Development of Sichuan Education Department, Sichuan Industrial Institute of Antibiotics, School of Pharmacy, Chengdu University, Chengdu, China.
Abstract:
SBFI26, an inhibitor of FABP5, has been shown to suppress the proliferation and metastasis of tumour cells. However, the underlying mechanism by which SBFI26 induces ferroptosis in breast cancer cells remains largely unknown. Three breast cancer cell lines were treated with SBFI26 and CCK-8 assessed cytotoxicity. Transcriptome was performed on the Illumina platform and verified by qPCR. Western blot evaluated protein levels. Malondialdehyde (MDA), total superoxide dismutase (T-SOD), Fe, glutathione (GSH) and oxidized glutathione (GSSG) were measured. SBFI26 induced cell death time- and dose-dependent, with a more significant inhibitory effect on MDA-MB-231 cells. Fer-1, GSH and Vitamin C attenuated the effects but not erastin. RNA-Seq analysis revealed that SBFI26 treatment significantly enriched differentially expressed genes related to ferroptosis. Furthermore, SBFI26 increased intracellular MDA, iron ion, and GSSG levels while decreasing T-SOD, total glutathione (T-GSH), and GSH levels.SBFI26 dose-dependently up-regulates the expression of HMOX1 and ALOX12 at both gene and protein levels, promoting ferroptosis. Similarly, it significantly increases the expression of SAT1, ALOX5, ALOX15, ALOXE3 and CHAC1 that, promoting ferroptosis while downregulating the NFE2L2 gene and protein that inhibit ferroptosis. SBFI26 leads to cellular accumulation of fatty acids, which triggers excess ferrous ions and subsequent lipid peroxidation for inducing ferroptosis.
Insights
SBFI26, a fatty acid-binding protein 5 (FABP5) inhibitor, induces breast cancer cell death via ferroptosis. It increases iron and lipid peroxidation, suppressing tumor growth by upregulating ferroptosis-promoting genes.
Area of Science:
- Oncology
- Biochemistry
- Molecular Biology
Background:
- SBFI26 inhibits FABP5 and suppresses tumor cell proliferation and metastasis.
- The mechanism of SBFI26-induced ferroptosis in breast cancer is not well understood.
Purpose of the Study:
- To elucidate the mechanism by which SBFI26 induces ferroptosis in breast cancer cells.
Main Methods:
- Cell viability was assessed using CCK-8 assays.
- Transcriptome analysis was performed using Illumina sequencing and validated by qPCR.
- Protein levels were evaluated by Western blot, and levels of MDA, T-SOD, Fe, GSH, and GSSG were measured.
Main Results:
- SBFI26 induced time- and dose-dependent cell death, notably in MDA-MB-231 cells.
- Fer-1, GSH, and Vitamin C attenuated SBFI26 effects, while erastin did not.
- SBFI26 increased intracellular MDA, iron, and GSSG, while decreasing T-SOD, T-GSH, and GSH.
- SBFI26 upregulated ferroptosis-promoting genes (HMOX1, ALOX12, SAT1, ALOX5, ALOX15, ALOXE3, CHAC1) and downregulated the inhibitor NFE2L2.
- SBFI26 caused fatty acid accumulation, leading to iron overload and lipid peroxidation.
Conclusions:
- SBFI26 effectively induces ferroptosis in breast cancer cells.
- The mechanism involves iron accumulation, lipid peroxidation, and modulation of key ferroptosis-related genes.
- SBFI26 shows potential as a therapeutic agent for breast cancer.
