RT Journal Article
SR Electronic
T1 Conjugated linolenic fatty acids trigger ferroptosis in triple-negative breast cancer
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 556084
DO 10.1101/556084
A1 Alexander Beatty
A1 Tanu Singh
A1 Yulia Y. Tyurina
A1 Emmanuelle Nicolas
A1 Kristen Maslar
A1 Yan Zhou
A1 Kathy Q. Cai
A1 Yinfei Tan
A1 Sebastian Doll
A1 Marcus Conrad
A1 Hülya Bayır
A1 Valerian E. Kagan
A1 Ulrike Rennefahrt
A1 Jeffrey R. Peterson
YR 2019
UL http://biorxiv.org/content/early/2019/02/20/556084.abstract
AB Ferroptosis is a non-apoptotic form of cell death linked to the accumulation of reactive hydroperoxides generated by oxidation of polyunsaturated fatty acids (PUFAs) in membrane phospholipids. The therapeutic potential of promoting ferroptosis by enriching PUFAs in cancer cells is unknown. We found an association between elevated PUFA levels and vulnerability to ferroptosis in triple-negative breast cancer (TNBC) cells. A screen of PUFAs identified conjugated linolenic acids, including α-eleostearate, as ferroptosis inducers. Three conjugated double bonds were required for ferroptotic activity although their positioning and stereochemistry were less significant. Mechanistically, α-eleostearate differed from canonical ferroptosis inducers by a distinct dependence on acyl-CoA synthetase long-chain isoforms and by not altering glutathione or glutathione peroxidase 4 activity. Orally administered tung oil, naturally rich in α-eleostearate, limited tumor growth and metastasis in an aggressive TNBC xenograft model. These results expand our understanding of ferroptotic cell death and highlight the anti-cancer potential of conjugated PUFAs.