The Combined Inhibition of Autophagy and Diacylglycerol Acyltransferase-Mediated Lipid Droplet Biogenesis Induces Cancer Cell Death during Acute Amino Acid Starvation.

Lipid droplets (LDs) are dynamic organelles involved in the management of fatty acid trafficking and metabolism. Recent studies suggest that autophagy and LDs serve complementary roles in the protection against nutrient stress, but the autophagy-LD interplay in cancer cells is not well understood. Here, we examined the relationship between autophagy and LDs in starving HeLa cervical cancer- and MDA-MB-231 breast cancer cells. We found that acute amino acid depletion induces autophagy and promotes diacylglycerol acyltransferase 1 (DGAT1)-mediated LD accumulation in HeLa cells. Inhibition of autophagy via late-stage autophagy inhibitors, or by knocking down autophagy-related 5 (ATG5), reduced LD accumulation in amino acid-starved cancer cells, suggesting that autophagy contributes to LD biogenesis. On the contrary, knockdown of adipose triglyceride lipase (ATGL) increased LD accumulation, suggesting that LD breakdown is mediated by lipolysis under these conditions. Concurrent inhibition of autophagy by silencing ATG5 and of LD biogenesis using DGAT inhibitors was effective in killing starving HeLa cells, whereas cell survival was not compromised by suppression of ATGL-mediated lipolysis. Autophagy-dependent LD biogenesis was also observed in the aggressive triple-negative MDA-MB-231 breast cancer cells deprived of amino acids, but these cells were not sensitized to starvation by the combined inhibition of LD biogenesis and autophagy. These findings reveal that while targeting autophagy-driven and DGAT-mediated LD biogenesis reduces the resilience of HeLa cervical cancer cells to amino acid deprivation, this strategy may not be successful in other cancer cell types.

Lipid Droplets in Cancer: Guardians of Fat in a Stressful World.

Cancer cells possess remarkable abilities to adapt to adverse environmental conditions. Their survival during severe nutrient and oxidative stress depends on their capacity to acquire extracellular lipids and the plasticity of their mechanisms for intracellular lipid synthesis, mobilisation, and recycling. Lipid droplets, cytosolic fat storage organelles present in most cells from yeast to men, are emerging as major regulators of lipid metabolism, trafficking, and signalling in various cells and tissues exposed to stress. Their biogenesis is induced by nutrient and oxidative stress and they accumulate in various cancers. Lipid droplets act as switches that coordinate lipid trafficking and consumption for different purposes in the cell, such as energy production, protection against oxidative stress or membrane biogenesis during rapid cell growth. They sequester toxic lipids, such as fatty acids, cholesterol and ceramides, thereby preventing lipotoxic cell damage and engage in a complex relationship with autophagy. Here, we focus on the emerging mechanisms of stress-induced lipid droplet biogenesis; their roles during nutrient, lipotoxic, and oxidative stress; and the relationship between lipid droplets and autophagy. The recently discovered principles of lipid droplet biology can improve our understanding of the mechanisms that govern cancer cell adaptability and resilience to stress.