Adiponectin triggers breast cancer cell death via fatty acid metabolic reprogramming.

Adiponectin, the most abundant adipokine derived from adipose tissue, exhibits a potent suppressive effect on the growth of breast cancer cells; however, the underlying molecular mechanisms for this effect are not completely understood. Fatty acid metabolic reprogramming has recently been recognized as a crucial driver of cancer progression. Adiponectin demonstrates a wide range of metabolic activities for the modulation of lipid metabolism under physiological conditions. However, the biological actions of adiponectin in cancer-specific lipid metabolism and its role in the regulation of cancer cell growth remain elusive. The effects of adiponectin on fatty acid metabolism were evaluated by measuring the cellular neutral lipid pool, free fatty acid level, and fatty acid oxidation (FAO). Colocalization between fluorescent-labeled lipid droplets and LC3/lysosomes was employed to detect lipophagy activation. Cell viability and apoptosis were examined by MTS assay, caspase-3/7 activity measurement, TUNEL assay, and Annexin V binding assay. Gene expression was determined by real time-quantitative polymerase chain reaction (RT-qPCR) and western blot analysis. The transcriptional activity of SREBP-1 was examined by a specific dsDNA binding assay. The modulatory roles of SIRT-1 and adiponectin-activated mediators were confirmed by gene silencing and/or using their pharmacological inhibitors. Observations from in vitro assays were further validated in an MDA-MB-231 orthotopic breast tumor model. Globular adiponectin (gAcrp) prominently decreased the cellular lipid pool in different breast cancer cells. The cellular lipid deficiency promoted apoptosis by causing disruption of lipid rafts and blocking raft-associated signal transduction. Mechanistically, dysregulated cellular lipid homeostasis by adiponectin was induced by two concerted actions: 1) suppression of fatty acid synthesis (FAS) through downregulation of SREBP-1 and FAS-related enzymes, and 2) stimulation of lipophagy-mediated lipolysis and FAO. Notably, SIRT-1 induction critically contributed to the adiponectin-induced metabolic alterations. Finally, fatty acid metabolic remodeling by adiponectin and the key role of SIRT-1 were confirmed in nude mice bearing breast tumor xenografts. This study elucidates the multifaceted role of adiponectin in tumor fatty acid metabolic reprogramming and provides evidence for the connection between its metabolic actions and suppression of breast cancer.