Docosahexaenoic acid monoglyceride induces apoptosis and autophagy in breast cancer cells via lipid peroxidation-mediated endoplasmic reticulum stress

Epidemiologic and preclinical studieshave shown that marine n-3 polyunsaturated fatty acids (n-3 PUFAs) elicit promising chemoprevention against breast Cancer. Docosahexaenoic acid monoglyceride (MAG-DHA), a docosahexaenoic acid sn-1-monoacylglycerol does not required pancreatic Lipase to be absorbed, eliciting a better bioavailability when compared with other formulations such as DHA-free fatty acid, DHA-triglycerol, or DHA-ethyl ester. However, the Anticancer actions and underlying mechanisms of MAG-DHA on breast Cancer remain to be assessed. In this study, MAG-DHA induced significant growth inhibition in MCF-7 and MDA-MB-231 breast Cancer cells in a dose-dependent manner. MAG-DHA treatment (80 µM) led to 83.8 and 94.3% growth inhibition between MCF-7 and MDA-MB-231 cells, respectively. MAG-DHA-induced growth inhibition was tightly associated with Apoptosis, as evidenced by increased active forms of Caspase-3, poly (ADP-ribose) polymerase (PARP) and caspase-12. In particular, MAG-DHA-induced Apoptosis was triggered by oxidative stress-mediated endoplasmic reticulum (ER) stress, as evidenced by activation of the PERK-eIF2α pathway in ER. MAG-DHA treatment also strongly suppressed the growth of E0771 murine breast Cancer xenografts, significant differences of tumor volume were found between MAG-DHA group (0.271 cm³ ) and control group (0.875 cm³ ) after 15 daily MAG-DHA treatments. The in vitro antibreast Cancer mechanism of MAG-DHA was supported by the in vivo xenograft model. In addition, MAG-DHA-induced ER stress concomitantly triggered Autophagy in these Cancer cells, and the induction of Autophagy suppressed its ability to induce apoptotic cell death. Our data suggested that MAG-DHA as dietary supplement, in combination with Autophagy inhibitors may be a useful therapeutic strategy in treating breast Cancer.