Abstract
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.
Highlights
Breast cancer is by far the most frequently diagnosed cancer among women across the globe, with over 2 million new cases estimated in 2018
As shown in Fig. 1E&F, NF-E2-related factor 2 (Nrf2) and HO-1, two crucial components of cellular oxidative stress response were significantly up-regulated in MCF-7 and MDA-MB-231 cells treated with MAG-DHA
We found that the protein levels of phosphorylated protein kinase R-like ER kinase (PERK), a major transducer of endoplasmic reticulum (ER) stress and phosphorylated eiF2α, a downstream target of PERK were significantly increased in MCF-7 and MDA-MB-231 cells treated with MAG-DHA, the total amount of PERK and eiF2α did not change (Fig. 2A&B)
Summary
Breast cancer is by far the most frequently diagnosed cancer among women across the globe, with over 2 million new cases estimated in 2018. Studies have shown that MAG-DHA, a DHA sn-1-monoacylglyceroldoes not required pancreatic lipase to be absorbed, unlike DHA-triglyceride which needs to behydrolyzed by sn1,3’specificgastric and (colipase-dependent) pancreatic lipases as free fatty acids and monoglycerol prior to intestinal absorption. This property confers increased absorption, and a better bioavailability when compared with other formulations such as DHA-triglycerol (TAG-DHA), or DHA-ethyl ester (EE-DHA)(Fortin 21 February, 2012; Fortin 17 July, 2012). The specific objective was to evaluate the effect of MAG-DHA on tumor growth and its underlying molecular mechanisms using an in vitro model of breast cancer cell lineMCF-7 and MDA-MB-231and an in vivo mouse model of E0771 xenograft
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