Docosahexaenoic acid supresses breast cancer cell proliferation and migration by promoting the expression of miR-99a and targeting mTOR signaling

Abstract

Docosahexaenoic acid (DHA) shows different anti-cancer effects on breast cancer (BC) cell proliferation and progression; however, the underlying molecular mechanism yet still is blanketed in mystery. Herein, we aimed to reveal whether the inhibitory effects of DHA on BC proliferation and migration are exerted, at least in part, through promoting the expression of miR-99a and targeting mTOR signaling. DHA lessened the BC cell viability in a time- and concentration-dependent manner. Besides, DHA-treatment significantly suppressed the proliferation and migration, while promoted BC cell apoptosis by regulating Bax and Bcl-2. We also demonstrated that DHA activated caspase-3/7 in MDA-MB-231 BCE cells. Also, we determined that miR-99a was upregulated in DHA-treated cells and mTOR was a direct and functional target of this miRNA, verified by the ability of anti-miR-99a to rescue the suppressive effects of DHA on mTOR expression in BC cells. Furthermore, DHA was shown to inhibit the mTOR-HIF-1α-VEGF signaling via regulating miR-99a in BC cells. DHA treatment caused a significant dose-dependent reduction of VEGF secretion from BC cells. When miR-99a was knocked down, DHA did not inhibit the BC proliferation and migration. We concluded that the anti-cancer effects of DHA can be attributed to the up-regulation of miR-99a that ipso facto inhibit the mTOR-HIF-1α-VEGF axis in BC cells. It is thought that DHA treatment might be considered as a promising supplement for BC therapy.