Alexander Beatty1, Tanu Singh2, Yulia Y Tyurina3,4, Vladimir A Tyurin3,4, Svetlana Samovich3,4, Emmanuelle Nicolas2, Kristen Maslar5, Yan Zhou2, Kathy Q Cai2, Yinfei Tan2, Sebastian Doll6, Marcus Conrad6,7, Aravind Subramanian8, Hülya Bayır3,4,9, Valerian E Kagan3,4,10,11,12,13, Ulrike Rennefahrt14, Jeffrey R Peterson15. 1. Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA. Alexander.Beatty@fccc.edu. 2. Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA. 3. Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA, USA. 4. Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA, USA. 5. Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA, USA. 6. Institute of Metabolism and Cell Death, Helmholtz Zentrum München, Neuherberg, Germany. 7. National Research Medical University, Laboratory of Experimental Oncology, Ostrovityanova 1, Moscow, 117997, Russia. 8. Broad Institute of Harvard and MIT, Cambridge, MA, USA. 9. Department of Critical Care Medicine, Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA, USA. 10. Department of Chemistry, University of Pittsburgh, Pittsburgh, PA, USA. 11. Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA. 12. Department of Radiation Oncology, University of Pittsburgh, Pittsburgh, PA, USA. 13. Laboratory of Navigational Redox Lipidomics, IM Sechenov Moscow State Medical University, Moscow, Russia. 14. Metanomics Health GmbH, Berlin, Germany. 15. Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA. Jeffrey.Peterson@fccc.edu.
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 α-eleostearic acid (αESA) as ferroptosis inducers. αESA does not alter GPX4 activity but is incorporated into cellular lipids and promotes lipid peroxidation and cell death in diverse cancer cell types. αESA-triggered death is mediated by acyl-CoA synthetase long-chain isoform 1, which promotes αESA incorporation into neutral lipids including triacylglycerols. Interfering with triacylglycerol biosynthesis suppresses ferroptosis triggered by αESA but not by GPX4 inhibition. Oral administration of tung oil, naturally rich in αESA, 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.
Ferroptosis is associated with lipid hydroperoxides genepan class="Species">rated 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 α-eleostearic acid (αESA) as ferroptosis inducers. αESA does not alter GPX4 activity but is incorporated into cellular lipids and promotes lipidperoxidation and cell death in diverse cancer cell types. αESA-triggered death is mediated by acyl-CoA synthetase long-chain isoform 1, which promotes αESA incorporation into neutral lipids including triacylglycerols. Interfering with triacylglycerol biosynthesis suppresses ferroptosis triggered by αESA but not by GPX4 inhibition. Oral administration of tung oil, naturally rich in αESA, 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.
Authors: Sebastian Doll; Florencio Porto Freitas; Ron Shah; Maceler Aldrovandi; Milene Costa da Silva; Irina Ingold; Andrea Goya Grocin; Thamara Nishida Xavier da Silva; Elena Panzilius; Christina H Scheel; André Mourão; Katalin Buday; Mami Sato; Jonas Wanninger; Thibaut Vignane; Vaishnavi Mohana; Markus Rehberg; Andrew Flatley; Aloys Schepers; Andreas Kurz; Daniel White; Markus Sauer; Michael Sattler; Edward William Tate; Werner Schmitz; Almut Schulze; Valerie O'Donnell; Bettina Proneth; Grzegorz M Popowicz; Derek A Pratt; José Pedro Friedmann Angeli; Marcus Conrad Journal: Nature Date: 2019-10-21 Impact factor: 49.962
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Authors: Marcus Conrad; Valerian E Kagan; Hülya Bayir; Gabriela C Pagnussat; Brian Head; Maret G Traber; Brent R Stockwell Journal: Genes Dev Date: 2018-05-01 Impact factor: 11.361
Authors: Kirill Bersuker; Joseph M Hendricks; Zhipeng Li; Leslie Magtanong; Breanna Ford; Peter H Tang; Melissa A Roberts; Bingqi Tong; Thomas J Maimone; Roberto Zoncu; Michael C Bassik; Daniel K Nomura; Scott J Dixon; James A Olzmann Journal: Nature Date: 2019-10-21 Impact factor: 49.962
Authors: Michael M Gaschler; Alexander A Andia; Hengrui Liu; Joleen M Csuka; Brisa Hurlocker; Christopher A Vaiana; Daniel W Heindel; Dylan S Zuckerman; Pieter H Bos; Eduard Reznik; Ling F Ye; Yulia Y Tyurina; Annie J Lin; Mikhail S Shchepinov; Amy Y Chan; Eveliz Peguero-Pereira; Maksim A Fomich; Jacob D Daniels; Andrei V Bekish; Vadim V Shmanai; Valerian E Kagan; Lara K Mahal; K A Woerpel; Brent R Stockwell Journal: Nat Chem Biol Date: 2018-04-02 Impact factor: 15.040