Defining a Water-Soluble Formulation of Arachidonic Acid as a Novel Ferroptosis Inducer in Cancer Cells
- Author(s)
- Day, ZI; Mayfosh, AJ; Baxter, AA; Williams, SA; Hildebrand, JM; Rau, TF; Poon, IKH; Hulett, MD;
- Details
- Publication Year 2024-05-04,Volume 14,Issue #5,Page 555
- Journal Title
- Biomolecules
- Abstract
- Here, we describe GS-9, a novel water-soluble fatty acid-based formulation comprising L-lysine and arachidonic acid, that we have shown to induce ferroptosis. GS-9 forms vesicle-like structures in solution and mediates lipid peroxidation, as evidenced by increased C11-BODIPY fluorescence and an accumulation of toxic malondialdehyde, a downstream product of lipid peroxidation. Ferroptosis inhibitors counteracted GS-9-induced cell death, whereas caspase 3 and 7 or MLKL knock-out cell lines are resistant to GS-9-induced cell death, eliminating other cell death processes such as apoptosis and necroptosis as the mechanism of action of GS-9. We also demonstrate that through their role of sequestering fatty acids, lipid droplets play a protective role against GS-9-induced ferroptosis, as inhibition of lipid droplet biogenesis enhanced GS-9 cytotoxicity. In addition, Fatty Acid Transport Protein 2 was implicated in GS-9 uptake. Overall, this study identifies and characterises the mechanism of GS-9 as a ferroptosis inducer. This formulation of arachidonic acid offers a novel tool for investigating and manipulating ferroptosis in various cellular and anti-cancer contexts.
- Publisher
- MDPI
- Keywords
- *Ferroptosis/drug effects; *Arachidonic Acid/metabolism/pharmacology; Humans; Lipid Peroxidation/drug effects; Cell Line, Tumor; Water/chemistry; Solubility; Neoplasms/metabolism/drug therapy/pathology/genetics; Lipid Droplets/metabolism/drug effects; L-lysine; arachidonic acid; cancer; cell death; fatty acids; ferroptosis
- Research Division(s)
- Inflammation
- PubMed ID
- 38785962
- Publisher's Version
- https://doi.org/10.3390/biom14050555
- Open Access at Publisher's Site
https://doi.org/10.3390/biom14050555- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2024-06-24 11:29:51
Last Modified: 2024-06-24 11:44:27