BETi enhance ATGL expression and its lipase activity to exert their antitumoral effects in triple-negative breast cancer (TNBC) cells.

The anti-proliferative effect achieved by BETi is helped by ATGL mediating lipolysis. This study showed that BETi altered the mitochondrial dynamics taking advantage of ATGL function to induce cell cycle arrest and cell death. Schematic representation of BETi mechanism of action on ATGL in TNBC cells. BETi induce the expression of FoxO1 and ATGL, lowering the expression of G0G2, leading to a switch in metabolic status. The induced expression of ATGL leads to increased lipolysis and a decrease in lipid droplet content and bioavailability of neutral lipid. At the same time, the mitochondria are enriched with fatty acids. This cellular status inhibits cell proliferation and increases ROS production and mitochondrial stress. Interfering for ATGL expression, the oxidative phenotypic status mildly reverted to a glycolytic status where neutral lipids are stored into lipid droplets with a consequent reduction of oxidative stress in the mitochondrial.