Journal article
Ferroptotic cell death triggered by conjugated linolenic acids is mediated by ACSL1
NATURE COMMUNICATIONS, v 12(1), 2244
14 Apr 2021
PMID: 33854057
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Ferroptosis is associated with lipid hydroperoxides generated by the oxidation of polyunsaturated acyl chains. Lipid hydroperoxides are reduced by glutathione peroxidase 4 (GPX4) and GPX4 inhibitors induce ferroptosis. However, the therapeutic potential of triggering ferroptosis in cancer cells with polyunsaturated fatty acids is unknown. Here, we identify conjugated linoleates including alpha -eleostearic acid (alpha ESA) as ferroptosis inducers. alpha ESA does not alter GPX4 activity but is incorporated into cellular lipids and promotes lipid peroxidation and cell death in diverse cancer cell types. alpha ESA-triggered death is mediated by acyl-CoA synthetase long-chain isoform 1, which promotes alpha ESA incorporation into neutral lipids including triacylglycerols. Interfering with triacylglycerol biosynthesis suppresses ferroptosis triggered by alpha ESA but not by GPX4 inhibition. Oral administration of tung oil, naturally rich in alpha ESA, to mice limits tumor growth and metastasis with transcriptional changes consistent with ferroptosis. Overall, these findings illuminate a potential approach to ferroptosis, complementary to GPX4 inhibition. Inhibition of the lipid peroxidase GPX4 promotes ferroptotic cell death. Here, the authors identify a complementary approach using conjugated linolenic fatty acids that trigger lipid peroxidation and ferroptosis via ACSL1, DGAT1/2, and neutral lipids.
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Details
- Title
- Ferroptotic cell death triggered by conjugated linolenic acids is mediated by ACSL1
- Publication Details
- NATURE COMMUNICATIONS, v 12(1), 2244
- Publisher
- NATURE RESEARCH; BERLIN
- Grant note
- This work was supported in part by the Office of the Assistant Secretary of Defense for Health Affairs through the Breast Cancer Research Program of the CDMRP under Award No. W81XWH-19-1-0481. Additional support was provided by National Institutes of Health Awards GM083025, U19AI068021, HL114453-06, CA165065-06, NS076511, the PA Breast Cancer Coalition, the Fifth District AHEPA Cancer Research Foundation, the Spurlino Family Foundation, the Rita Hollman Foundation, the Eileen Stein Jacoby Fund, and Translational Research and In Vino Vita awards from Fox Chase Cancer Center. Supported in part by Award Number P30 CA006927 from the National Cancer Institute of the National Institutes of Health. We thank Drs. S. Balachandran and J. Karanicolas for comments on the manuscript.
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Drexel University
- Web of Science ID
- WOS:000640561300008
- Scopus ID
- 2-s2.0-85104482206
- Other Identifier
- 991021860666704721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology