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

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.

Punicic Acid Triggers Ferroptotic Cell Death in Carcinoma Cells

“…As indicated by our results as well as by other in vitro and in vivo studies [ 1 , 49 ], CLnAs are phytochemicals with promising anti-cancer effects that could be exploited as preventive or even therapeutic agents. CLnAs are mainly found in seed oils of specific plants and the CLnA content can reach up to 80% of the total lipids [ 5 ], making CLnAs accessible nutritional phytochemicals.…”

“…Since ferroptosis relies on an extensive accumulation of PUFA-derived lipid peroxides [ 32 , 33 ], we assumed that PunA may trigger ferroptosis in carcinoma cells. Although some previous reports indicated that CLnAs are likely to trigger apoptosis [ 7 , 23 , 60 ], ferroptosis has recently appeared as a potent cell death pathway underlying CLnA cytotoxicity on cancer cells [ 49 ]. In the present study, we evaluated the impact of two ferroptosis inhibitors, namely ferrostatin-1 (fer-1) and α-tocopherol (α-T), on the cytotoxicity of PunA on HCT-116 and FaDu carcinoma cells.…”

“…Indeed, the conjugated structure of CLnAs confers them a chemical specificity that lipid enzymes could tackle differently as compared to unconjugated PUFAs. Interestingly, Beatty et al showed that the incorporation of α-ESA into neutral lipids is responsible for its pro-ferroptotic effect [ 49 ]. However, the different CLnA isomers have been documented to be distributed differently between neutral lipids and phospholipids based on their number of trans double bonds, suggesting that the cytotoxicity of specific CLnA isomers may be due to their incorporation into selective lipid species [ 5 ].…”

“…In fact, several lines of research suggest that a wide range of PUFAs might sensitize cancer cells to ferroptosis by causing a dramatic accumulation of phospholipid-derived peroxides [37,[46][47][48]. A very recent study conducted by Beatty et al showed that upon incorporation into triglycerides, α-ESA triggers ferroptosis in triple negative breast cancer cells [49]. This study however is at odds with previous work from our team, where we reported that triglyceride storage has a protective effect against PUFA-induced ferroptosis [50].…”

“…It is indeed present in large amounts in pomegranate seed oil [ 6 ], the only CLnA-rich oil widely recognized as edible on the market [ 14 ]. While tung oil intake (as used in the study of Beatty et al [ 49 ]) has been associated with toxic effects in vivo [ 51 ], the consumption of pomegranate seed oil has demonstrated no detrimental effects on body functions nor on tissue homeostasis [ 17 , 52 ].…”