Conjugated linolenic fatty acids trigger ferroptosis in triple-negative breast cancer

Abstract

Recent studies have shown that cancer cells, including renal cell carcinoma, melanoma and glioblastoma are vulnerable to ferroptosis [10][11][12][13][14][15][16] . Furthermore therapy-resistant mesenchymal cancer cells exhibit a greater reliance on GPX4 activity for survival 10,17 . These findings have highlighted the therapeutic potential of pro-ferroptotic agents, but it remains unclear whether induction of ferroptosis can be used therapeutically to selectively kill cancer cells in vivo 1 . A major challenge to testing this hypothesis has been the absence of selective ferroptosis-inducing agents, such as GPX4 inhibitors, suitable for use in vivo 18 .While suppressing the GPX4-mediated antioxidant response is one approach to induce ferroptosis, a complementary approach is to promote the production of lipid hydroperoxides by increasing the availability of their PUFA precursors. Hydroperoxides can spread by a free radical-mediated chain reaction leading to oxidation of adjacent PUFAs, and consequently higher PUFA levels could increase vulnerability to the propagation of lipid peroxides. Indeed, supplementation of cells with the PUFA arachidonic acid sensitizes them to ferroptosis triggered by GPX4 inhibitors 19 . Importantly, this approach to enhancing ferroptosis would exploit the propensity of cancer cells to scavenge fatty acids from their environment 20 .Here we report a vulnerability in triple-negative breast cancer (TNBC) to ferroptosis associated with the accumulation of PUFAs, and identified conjugated linolenic fatty acids as PUFAs that induce ferroptosis.Mechanistically, accumulation of PUFAs in TNBC triggered ferroptosis by a mode of action distinct from canonical ferroptosis inducers. We show that oral administration of tung nut oil, naturally rich in the conjugated PUFA α-eleostearate, has anti-cancer activity in a xenograft model of TNBC. α-Eleostearate metabolites could be detected in tumors of treated mice and was associated with expression of ferroptotic markers. These results introduce a distinct class of ferroptosis inducers and offer novel insights into the molecular basis of ferroptotic sensitivity. The tractability of these dietary, pro-ferroptotic fatty acids addresses the current lack of effective GPX4 inhibitors for use in vivo and suggests a novel opportunity to exploit a metabolic liability in an aggressive breast cancer subtype.

Targeting ferroptosis in breast cancer

“…Beatty et al found that the conjugated linoleic acid (LA) α-eleostearic acid induced ferroptosis in TNBC, depending on acyl-CoA synthetase long-chain isoforms other than glutathione or GPX4 activity. In contrast to the previous study, the authors highlighted that three conjugated double bonds in the conjugated LA were required for ferroptotic activity, while their positioning and stereochemistry were less important [82].…”

“…Apoptosis and ferroptosis can be induced by a common mechanism in breast cancer. As described above, PUFAs can induce ferroptosis in an ACSL4-dependent manner, and induce apoptosis via the peroxisome proliferator-activated receptor gamma (PPARγ)/SDC-1 pathway [82,115]. Lipid peroxidation is the main killer in the process of ferroptosis, which could derive from lipids by being "attacked" by intracellular ROS [18].…”

Therapy-induced lipid uptake and remodeling underpin ferroptosis hypersensitivity in prostate cancer

“…5d). Recent work showed that exogenous PUFAs can sensitize triple negative breast cancer to ferroptosis [77]. If not enzymatically repaired by GPX4 at the expense of reduced glutathione, accumulation of lipid hydroperoxides can lead to cell death via ferroptosis.…”

“…More importantly, the diversity of targeted therapies causing this shared GPX4 dependence suggests that lipid remodeling leading to PUFA enrichment of phospholipids might be a common mechanism associated with therapy resistance that could be pursued as therapeutic target in multiple types of cancer. However, the treatment window of therapy-induced ferroptosis hypersensitivity is likely to be restricted to the low cycling, quiescence phase [9] because high membrane PUFA levels sensitize to ferroptosis [77] and would limit proliferation rates [48] due to the increased lipid peroxidation stress generated by higher metabolic activities and associated ROS production. Such stress would be further aggravated by higher demands in reducing power (NADPH) for the recycling of oxidized glutathione and de novo lipid synthesis.…”

Host phospholipid peroxidation fuels ExoU-dependent cell necrosis and supports Pseudomonas aeruginosa-driven pathology

“…These results suggest that, instead of promoting pathological lipid peroxidation, ExoU might actually use cellular lipid peroxidation to promote cell necrosis. To this regard, various host phospholipase A2 enzymes have been described to specifically cleave and remove peroxidised phospholipids from membranes [60][61][62]. To address this hypothesis, we performed a redox phospholipidomic approach to determine if ExoU could interfere with the endogenous levels of peroxidised phospholipids (Figs 3B and S3C).…”