Berberine induces mitochondrial apoptosis of EBV-transformed B cells through p53-mediated regulation of XAF1 and GADD45α.
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 B cells or cancerous B cells after treatment with berberine. Berberine decreased cell viability and induced apoptosis through a mitochondria-dependent pathway in EBV-transformed B cells and cancerous B cells, 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 B cells through the upregulation of XAF1 and GADD45α expression by MAPK and functional p53.
Department of Biochemistry, Kosin University College of Medicine, Busan 49267, Republic of Korea.
Ga Bin
GB
Park
Department of Urology, Inje University Haeundae Paik Hospital, Busan 48108, Republic of Korea.
Sang Hyun
SH
Park
Department of Anatomy, Inje University College of Medicine, Busan 47392, Republic of Korea.
Daejin
D
Kim
Department of Anatomy, Inje University College of Medicine, Busan 47392, Republic of Korea.
Yeong Seok
YS
Kim
Department of Plastic Surgery, Inje University Haeundae Paik Hospital, Busan 48108, Republic of Korea.
Sung Ho
SH
Yoon
Department of Anatomy, Inje University College of Medicine, Busan 47392, Republic of Korea.
Dae Young
DY
Hur
D048868:Adaptor Proteins, Signal Transducing; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins; D001599:Berberine / Q000008:administration & dosage*; D018797:Cell Cycle Proteins / Q000096:biosynthesis* / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D002472:Cell Transformation, Viral / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D004854:Herpesvirus 4, Human / Q000235:genetics; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000096:biosynthesis* / Q000235:genetics; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000235:genetics; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics*; D048051:p38 Mitogen-Activated Protein Kinases / Q000096:biosynthesis / Q000235:genetics*; D000097642:GADD45 Proteins
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D001599:Berberine; D018797:Cell Cycle Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D048051:p38 Mitogen-Activated Protein Kinases; C439070:GADD45A protein, human; D000097642:GADD45 Proteins; C417551:XAF1 protein, human