Ferroptosis is a recently discovered form of regulated cell death that could be potentially used for anti-cancer therapy. Lipid droplets (LDs) and autophagy modulate the cellular distribution of polyunsaturated fatty acids (FAs), which are required for the execution of ferroptosis. Here, we investigated the role of LDs in breast cancer cells under ferroptotic conditions by promoting and inhibiting LD biogenesis with polyunsaturated FAs and pharmacological inhibitors of diacylglycerol acyltransferase (DGAT), respectively. Ferroptosis was induced with RSL3, inhibited with ferrostatin-1, and autophagy was blocked with bafilomycin A1. Using confocal microscopy, flow cytometry and protein immunodetection, we found that polyunsaturated FAs are not only required for ferroptosis, but they also induce ferroptosis in high concentrations. Ferroptotic stress induced DGAT-mediated LD biogenesis and decreases autophagic flux, but did not affect the expression of adipose triglyceride lipase (ATGL), the rate-limiting enzyme involved in LD lipolysis. We showed that inhibition of LD biogenesis increases, whereas inhibition of autophagy, at least in certain conditions, decreases the sensitivity of breast cancer cells to ferroptosis. Our work will contribute to the understanding of the connections between LDs, autophagy and ferroptosis and could help develop new strategies to reduce the resistance of cancer cells to stress.
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