Berberine induces mitochondrial apoptosis of EBV-transformed Bcells through p53-mediated regulation of XAF1 and GADD45α.

Abstract

Berberine exhibits antiproliferative or cytotoxic effects against various cancers. ROS and wild-type p53 play a critical role in berberine-induced cytotoxic effects. In this study, we investigated the correlation between XAF1 and functional p53 in EBV-transformed Bcells or cancerous Bcells after treatment with berberine. Berberine decreased cell viability and induced apoptosis through a mitochondria-dependent pathway in EBV-transformed Bcells and cancerous Bcells, but not in normal peripheral blood mononuclear cells. Activated p53 and its downstream targets XAF1 and GADD45α interacted with PUMA, Bax, and Bim in mitochondria after treatment with berberine. Blocking phosphorylation of p38/JNK MAPK and treatment with PFT-α, a selective p53 inhibitor, effectively prevented apoptosis and the upregulation of phosphorylated p53, XAF1, and GADD45α. NAC, a ROS scavenger, also suppressed berberine-induced mitochondria disruption and the whole apoptotic process via restoration of p53-related proteins and proapoptotic Bcl-2 family proteins. Taken together, our results suggest that ROS generation might be a predisposing event in berberine-induced mitochondrial apoptosis in EBV-transformed Bcells through the upregulation of XAF1 and GADD45α expression by MAPK and functional p53.