Fatostatin induces pro- and anti-apoptotic lipid accumulation in breast cancer.

Given the dependence of cancers on de novo lipogenesis, we tested the effect of fatostatin, a small molecule thought to target this pathway by blocking activation of SREBP transcription factors, in breast cancer cell lines and xenograft tumors. We found that estrogen receptor (ER) positive cells were more sensitive to fatostatin than ER negative cells and responded with cell cycle arrest and apoptosis. Surprisingly, we found that rather than inhibiting lipogenesis, fatostatin caused an accumulation of lipids as a response to endoplasmic reticulum stress rather than inhibition of SREBP activity. In particular, ceramide and dihydroceramide levels increased and contributed to the apoptotic effects of fatostatin. In addition, an accumulation of triacylglycerides (TAGs), particularly those containing polyunsaturated fatty acids (PUFAs), was also observed as a result of elevated diacylglycerol transferase activity. Blocking PUFA-TAG production enhanced the apoptotic effect of fatostatin, suggesting that these lipids play a protective role and limit fatostatin response. Together, these findings indicate that the ability of breast cancer cells to respond to fatostatin depends on induction of endoplasmic reticulum stress and subsequent ceramide accumulation, and that limiting production of PUFA-TAGs may be therapeutically beneficial in specific tumor subtypes.

Turning the Spotlight on Lipids in Non-Apoptotic Cell Death.

Although apoptosis has long dominated the spotlight, studies in the past two decades have expanded the repertoire of programmed cell death (PCD). Several forms of non-apoptotic regulated cell death have been identified, with important links to organismal homeostasis and different disease pathologies. Necroptosis, ferroptosis, pyroptosis, and NETosis are the major forms of PCD that have attracted attention. Clear biochemical distinctions differentiate these forms of non-apoptotic PCD at the protein and membrane levels. For instance, pore formation at the plasma membrane is a hallmark of necroptosis and pyroptosis; however, different proteins facilitate pore formation in these processes. Here, we will highlight the role of lipids in different forms of non-apoptotic PCD. In particular, we discuss how lipids can trigger or facilitate the membrane-related changes that result in cell death. We also highlight the use of small molecules in elucidating the mechanisms of non-apoptotic PCD and the potential of lipid biosynthetic pathways to perturb these processes for therapeutic applications as a future avenue of research.