Berberine‐Induced Cytotoxicity in Breast Cancer Is Mediated by Reversal of EMT and Repression of Sirtuin 1/AKT Signaling Pathways

Abstract

ABSTRACT Epithelial‐to‐mesenchymal transition (EMT) is an essential process by which tumor cells undergo metastasis. Berberine (Berb), a natural isoquinoline alkaloid, has exhibited antitumor properties against a wide range of cancer types. This study was conducted to investigate the underlying molecular mechanisms of the antitumor effect of berberine in the presence and absence of sirtuin‐1 inhibitor (sirtinol; Sirt) in vivo in mice bearing solid Ehrlich carcinoma (SEC) and in vitro in triple‐negative breast cancer (TNBC) cells. The mice were classified into four groups 12 days after the inoculation of SEC cells into the mice to induce breast cancer. These groups were as follows: the untreated SEC group (mice were administered the vehicle), the Sirt group (1 mg/kg), the Berb group (10 mg/kg), and the cotreatment Sirt/Berb group. For 16 days, they were administered on a daily basis. TNBC MDA‐MB‐231 cells were displayed in a 48‐h treatment containing 25 μM Sirt, 23 μM Berb, or a combination of the two. Berb and/or Sirt attenuated EMT as proven via the upregulation of E‐cadherin expression and downregulation of vimentin and sirtuin‐1 expression in both in vitro and in vivo experiments. These outcomes were correlated with reduced p‐AKT/AKT and vascular endothelial growth factor receptor 2 (VEGFR 2 ), along with retardation of cancer progression. The antitumor activity of Berb towards breast cancer was evidenced in vivo and in vitro and could be, in part, through EMT's inhibition and suppression of sirtuin‐1 and AKT cascades.