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Ferroptotic cell death triggered by conjugated linolenic acids is mediated by ACSL1

Beatty, Alexander, Singh, Tanu, Tyurina, Yulia Y., Tyurin, Vladimir A., Samovich, Svetlana, Nicolas, Emmanuelle, Maslar, Kristen, Zhou, Yan, Cai, Kathy Q., Tan, Yinfei, Doll, Sebastian, Conrad, Marcus, Subramanian, Aravind, Bayır, Hülya, Kagan, Valerian E., Rennefahrt, Ulrike, Peterson, Jeffrey R.·2021·Nature Communications
DOI 10.1038/s41467-021-22471-yPMC PMC8046803
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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.

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  1. Cao, J. Y. & Dixon, S. J. Mechanisms of ferroptosis. Cell Mol. Life Sci. 73, 2195–2209 (2016). · DOI · Paper page
  2. Yang, W. S. & Stockwell, B. R. Ferroptosis: death by lipid peroxidation. Trends Cell Biol. 26, 165–176 (2016). · DOI · Paper page
  3. Stockwell, B. R. et al. Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease. Cell 171, 273–285 (2017). · DOI · Paper page
  4. Friedmann-Angeli, J. P., Miyamoto, S. & Schulze, A. Ferroptosis: the greasy side of cell death. Chem. Res. Toxicol. 32, 362–369 (2019). · DOI
  5. Conrad, M. et al. Regulation of lipid peroxidation and ferroptosis in diverse species. Genes Dev. 32, 602–619 (2018). · DOI · Paper page
  6. Hassannia, B., Vandenabeele, P. & Vanden Berghe, T. Targeting ferroptosis to iron out cancer. Cancer Cell 35, 830–849 (2019). · DOI
  7. Conrad, M. & Friedmann Angeli, J. P. Glutathione peroxidase 4 (Gpx4) and ferroptosis: what’s so special about it? Mol. Cell Oncol. 2, e995047 (2015). · DOI
  8. Doll, S. et al. FSP1 is a glutathione-independent ferroptosis suppressor. Nature 575, 693–698 (2019). · DOI · Paper page
  9. Bersuker, K. et al. The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis. Nature 575, 688–692 (2019). · DOI · Paper page
  10. Gaschler, M. M. et al. FINO2 initiates ferroptosis through GPX4 inactivation and iron oxidation. Nat. Chem. Biol. 14, 507–515 (2018). · DOI
  11. Conrad, M. & Pratt, D. A. The chemical basis of ferroptosis. Nat. Chem. Biol. 15, 1137–1147 (2019). · DOI
  12. Wenzel, S. E. et al. PEBP1 wardens ferroptosis by enabling lipoxygenase generation of lipid death signals. Cell 171, 628–641 e26 (2017). · DOI
  13. Zou, Y. et al. Cytochrome P450 oxidoreductase contributes to phospholipid peroxidation in ferroptosis. Nat. Chem. Biol. 16, 302–309 (2020). · DOI
  14. Agmon, E., Solon, J., Bassereau, P. & Stockwell, B. R. Modeling the effects of lipid peroxidation during ferroptosis on membrane properties. Sci. Rep. 8, 5155 (2018). · DOI
  15. Kagan, V. E. et al. Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis. Nat. Chem. Biol. 18, 81–90 (2017). · DOI · Paper page
  16. Zou, Y. et al. A GPX4-dependent cancer cell state underlies the clear-cell morphology and confers sensitivity to ferroptosis. Nat. Commun. 10, 1617 (2019). · DOI · Paper page
  17. Magtanong, L. et al. Exogenous monounsaturated fatty acids promote a ferroptosis-resistant cell state. Cell Chem. Biol. 26, 420–432 e9 (2019). · DOI
  18. Tesfay, L. et al. Stearoyl-CoA desaturase 1 protects ovarian cancer cells from ferroptotic cell death. Cancer Res. 79, 5355–5366 (2019). · DOI
  19. Kamphorst, J. J. et al. Hypoxic and Ras-transformed cells support growth by scavenging unsaturated fatty acids from lysophospholipids. Proc. Natl Acad. Sci. USA 110, 8882–8887 (2013). · DOI · Paper page
  20. Beatty, A. et al. Metabolite profiling reveals the glutathione biosynthetic pathway as a therapeutic target in triple-negative breast cancer. Mol. Cancer Ther. 17, 264–275 (2018). · DOI
  21. Dixon, S. J. et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 149, 1060–1072 (2012). · DOI · Paper page
  22. Weiwer, M. et al. Development of small-molecule probes that selectively kill cells induced to express mutant RAS. Bioorg. Med. Chem. Lett. 22, 1822–1826 (2012). · DOI · Paper page
  23. Cui, P. et al. Tung Tree (Vernicia fordii, Hemsl.) genome and transcriptome sequencing reveals co-ordinate up-regulation of fatty acid beta-oxidation and triacylglycerol biosynthesis pathways during eleostearic acid accumulation in seeds. Plant Cell Physiol. 59, 1990–2003 (2018). · DOI
  24. Grossmann, M. E. et al. Eleostearic Acid inhibits breast cancer proliferation by means of an oxidation-dependent mechanism. Cancer Prev. Res. 2, 879–886 (2009). · DOI
  25. Kobori, M., Ohnishi-Kameyama, M., Akimoto, Y., Yukizaki, C. & Yoshida, M. Alpha-eleostearic acid and its dihydroxy derivative are major apoptosis-inducing components of bitter gourd. J. Agric Food Chem. 56, 10515–10520 (2008). · DOI
  26. Zhuo, R. J. et al. Alpha-eleostearic acid inhibits growth and induces apoptosis in breast cancer cells via HER2/HER3 signaling. Mol. Med. Rep. 9, 993–998 (2014). · DOI
  27. Obitsu, S., Sakata, K., Teshima, R. & Kondo, K. Eleostearic acid induces RIP1-mediated atypical apoptosis in a kinase-independent manner via ERK phosphorylation, ROS generation and mitochondrial dysfunction. Cell Death Dis. 4, e674 (2013). · DOI
  28. Chou, Y. C., Su, H. M., Lai, T. W., Chyuan, J. H. & Chao, P. M. cis-9, trans-11, trans-13-Conjugated linolenic acid induces apoptosis and sustained ERK phosphorylation in 3T3-L1 preadipocytes. Nutrition 28, 803–811 (2012). · DOI
  29. Zhang, T. et al. Growth inhibition and apoptotic effect of alpha-eleostearic acid on human breast cancer cells. J. Nat. Med. 66, 77–84 (2012). · DOI
  30. Yasui, Y. et al. Bitter gourd seed fatty acid rich in 9c,11t,13t-conjugated linolenic acid induces apoptosis and up-regulates the GADD45, p53 and PPARgamma in human colon cancer Caco-2 cells. Prostaglandins Leukot. Ess. Fat. Acids 73, 113–119 (2005). · DOI
  31. Yu, C. et al. High-throughput identification of genotype-specific cancer vulnerabilities in mixtures of barcoded tumor cell lines. Nat. Biotechnol. 34, 419–423 (2016). · DOI · Paper page
  32. Lubbock, A. L. R., Harris, L. A., Quaranta, V., Tyson, D. R. & Lopez, C. F. Visualization and analysis of high-throughput in vitro dose–response datasets with Thunor. bioRxiv (2019). · DOI
  33. Grevengoed, T. J., Klett, E. L. & Coleman, R. A. Acyl-CoA metabolism and partitioning. Annu Rev. Nutr. 34, 1–30 (2014). · DOI
  34. Wang, W. et al. Tissue-specific ablation of ACSL4 results in disturbed steroidogenesis. Endocrinology 160, 2517–2528 (2019). · DOI
  35. Li, L. O. et al. Overexpression of rat long chain acyl-coa synthetase 1 alters fatty acid metabolism in rat primary hepatocytes. J. Biol. Chem. 281, 37246–37255 (2006). · DOI · Paper page
  36. Conlon, M. et al. A compendium of kinetic cell death modulatory profiles identifies ferroptosis regulators. bioRxiv (2019). · DOI
  37. Do, Q. et al. Development and application of a peroxyl radical clock approach for measuring both hydrogen-atom transfer and peroxyl radical addition rate constants. J. Org. Chem. 86, 153–168 (2020). · DOI
  38. Garcia-Martinez, M. C., Marquez-Ruiz, G., Fontecha, J. & Gordon, M. H. Volatile oxidation compouds in a conjugated linoleic acid-rich oil. Food Chem. 113, 926–931 (2009). · DOI
  39. Kuge, Y., Kanda, A. & Hara, S. Pursuit of oxidation behavior for conjugated polyenoyl glycerols and establishment of their novel oxidation prevention method. J. Oleo Sci. 58, 295–301 (2009). · DOI
  40. Luna, P., de la Fuente, M. A., Salvador, D. & Marquez-Ruiz, G. Differences in oxidation kinetics between conjugated and non-conjugated methyl linoleate. Lipids 42, 1085–1092 (2007). · DOI
  41. Suzuki, R., Masayuki, A. & Miyashita, K. Comparative study of the autoxidation of TAG containing conjugated and nonconjugated C18 PUFA. J. Am. Oil Chem. Soc. 81, 563–569 (2004). · DOI
  42. Morita, M. & Tokita, M. Hydroxy radical, hexanal, and decadienal generation by autocatalysts in autoxidation of linoleate alone and with eleostearate. Lipids 43, 589–597 (2008). · DOI
  43. Dixon, S. J. et al. Pharmacological inhibition of cystine-glutamate exchange induces endoplasmic reticulum stress and ferroptosis. Elife 3, e02523 (2014). · DOI · Paper page
  44. Hassannia, B. et al. Nano-targeted induction of dual ferroptotic mechanisms eradicates high-risk neuroblastoma. J. Clin. Invest. 128, 3341–3355 (2018). · DOI
  45. Dhar Dubey, K. K., Sharma, G. & Kumar, A. Conjugated linolenic acids: implication in cancer. J. Agric Food Chem. 67, 6091–6101 (2019). · DOI
  46. Tsuzuki, T., Tokuyama, Y., Igarashi, M. & Miyazawa, T. Tumor growth suppression by alpha-eleostearic acid, a linolenic acid isomer with a conjugated triene system, via lipid peroxidation. Carcinogenesis 25, 1417–1425 (2004). · DOI
  47. Walther, T. C. & Farese, R. V. Jr Lipid droplets and cellular lipid metabolism. Annu Rev. Biochem. 81, 687–714 (2012). · DOI
  48. Bailey, A. P. et al. Antioxidant role for lipid droplets in a stem cell niche of drosophila. Cell 163, 340–353 (2015). · DOI
  49. Jarc, E. et al. Lipid droplets induced by secreted phospholipase A2 and unsaturated fatty acids protect breast cancer cells from nutrient and lipotoxic stress. Biochim Biophys. Acta Mol. Cell Biol. Lipids 1863, 247–265 (2018). · DOI
  50. Basu, S., Smedman, A. & Vessby, B. Conjugated linoleic acid induces lipid peroxidation in humans. FEBS Lett. 468, 33–36 (2000). · DOI
  51. Raff, M. et al. A diet rich in conjugated linoleic acid and butter increases lipid peroxidation but does not affect atherosclerotic, inflammatory, or diabetic risk markers in healthy young men. J. Nutr. 138, 509–514 (2008). · DOI
  52. Yamasaki, M. et al. Effect of dietary conjugated linoleic acid on lipid peroxidation and histological change in rat liver tissues. J. Agric Food Chem. 48, 6367–6371 (2000). · DOI
  53. Yang, L., Cao, Y., Chen, J. N. & Chen, Z. Y. Oxidative stability of conjugated linolenic acids. J. Agric Food Chem. 57, 4212–4217 (2009). · DOI
  54. Eom, J. M. et al. Alpha-eleostearic acid induces autophagy-dependent cell death through targeting AKT/mTOR and ERK1/2 signal together with the generation of reactive oxygen species. Biochem. Biophys. Res. Commun. 391, 903–908 (2010). · DOI
  55. Liu, J. et al. Autophagy-dependent ferroptosis: machinery and regulation. Cell Chem. Biol. 27, 420–435 (2020). · DOI
  56. Friedmann Angeli, J. P., Krysko, D. V. & Conrad, M. Ferroptosis at the crossroads of cancer-acquired drug resistance and immune evasion. Nat. Rev. Cancer 19, 405–414 (2019). · DOI
  57. Viswanathan, V. S. et al. Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway. Nature 547, 453–457 (2017). · DOI · Paper page
  58. Kyani, A. et al. Discovery and mechanistic elucidation of a class of protein disulfide isomerase inhibitors for the treatment of glioblastoma. ChemMedChem 13, 164–177 (2018). · DOI
  59. Buccarelli, M. et al. Inhibition of autophagy increases susceptibility of glioblastoma stem cells to temozolomide by igniting ferroptosis. Cell Death Dis. 9, 841 (2018). · DOI
  60. Chen, L. et al. Erastin sensitizes glioblastoma cells to temozolomide by restraining xCT and cystathionine-gamma-lyase function. Oncol. Rep. 33, 1465–1474 (2015). · DOI
  61. Feng, H. & Stockwell, B. R. Unsolved mysteries: How does lipid peroxidation cause ferroptosis? PLoS Biol. 16, e2006203 (2018). · DOI
  62. Soule, H. D. et al. Isolation and characterization of a spontaneously immortalized human breast epithelial cell line, MCF-10. Cancer Res 50, 6075–6086 (1990).
  63. Sampaio, J. L. et al. Membrane lipidome of an epithelial cell line. Proc. Natl Acad. Sci. USA 108, 1903–1907 (2011). · DOI
  64. Ejsing, C. S. et al. Global analysis of the yeast lipidome by quantitative shotgun mass spectrometry. Proc. Natl Acad. Sci. USA 106, 2136–2141 (2009). · DOI
  65. Surma, M. A. et al. An automated shotgun lipidomics platform for high throughput, comprehensive, and quantitative analysis of blood plasma intact lipids. Eur. J. Lipid Sci. Technol. 117, 1540–1549 (2015). · DOI
  66. Herzog, R. et al. A novel informatics concept for high-throughput shotgun lipidomics based on the molecular fragmentation query language. Genome Biol. 12, R8 (2011). · DOI
  67. Herzog, R. et al. LipidXplorer: a software for consensual cross-platform lipidomics. PLoS ONE 7, e29851 (2012). · DOI
  68. Sanjana, N. E., Shalem, O. & Zhang, F. Improved vectors and genome-wide libraries for CRISPR screening. Nat. Methods 11, 783–784 (2014). · DOI · Paper page
  69. Trapnell, C., Pachter, L. & Salzberg, S. L. TopHat: discovering splice junctions with RNA-Seq. Bioinformatics 25, 1105–1111 (2009). · DOI
  70. Trapnell, C. et al. Differential analysis of gene regulation at transcript resolution with RNA-seq. Nat. Biotechnol. 31, 46–53 (2013). · DOI · Paper page
  71. Watanabe, T. et al. A novel model of continuous depletion of glutathione in mice treated with L-buthionine (S,R)-sulfoximine. J. Toxicol. Sci. 28, 455–469 (2003). · DOI

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Metadata

Authors
Beatty, A., Singh, T., Tyurina, Y. Y., Tyurin, V. A., Samovich, S., Nicolas, E., Maslar, K., Zhou, Y., Cai, K. Q., Tan, Y., Doll, S., Conrad, M., Subramanian, A., Bayır, H., Kagan, V. E., Rennefahrt, U., & Peterson, J. R.
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2021-04-14
Volume
12
Issue
1
ISSN
2041-1723
DOI
10.1038/s41467-021-22471-y
PMC
PMC8046803
Cited by
268
References
12
Language
en
Licence
Funders
United States Department of Defense | United States Army | Army Medical Command | Congressionally Directed Medical Research Programs (W81XWH-19-1-0481)

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