Berberine induces mitochondrial apoptosis of EBV-transformed B cells 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 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.

Naturally occurring anti-cancer compounds: shining from Chinese herbal medicine

“…Several mechanisms have been identified for the anti-proliferative effects of berberine, including down-regulation of cyclins A, D, cyclin-dependent kinase (CDK) 1, CDK4, MMP-2 and janus kinase 2 (Jak2)/vascular endothelial growth factor (VEGF)/NF-κB/activator protein 1 (AP-1) pathway, and induction of autophagic cell death via mTOR signaling pathway [149,155,156]. Berberine also induces mitochondrial-mediated apoptosis through the loss of mitochondrial membrane potential, cytochrome c release, caspase and PARP activation, up-regulation of pro-apoptotic Bcl-2 family proteins, and down-regulation of antiapoptotic Bcl-2 family proteins [150,[157][158][159]. It can also activate apoptosis-inducing factor to induce ROSmediated cell death in pancreatic, breast, and colon cancers [158,160,161].…”

<p>The Anti-Cancer Mechanisms of Berberine: A Review</p>

“…34 BBR increased phosphorylation of p53 through activation of JNK/p38, which promoted the entry of the apoptotic proteins Bax and Bim into mitochondria. 35 In addition, studies showed that BBR promoted apoptosis through increased acetylation of foxo1/3a and increased expression of Bim and Bax. 36,37 In colon cancer cells, BBR promoted cell apoptosis by inducing the expression of ATF3 protein through increased p53 transcription activity.…”

DNA Oncogenic Virus‐Induced Oxidative Stress, Genomic Damage, and Aberrant Epigenetic Alterations

“…Exposure of EBV-infected cells correlates with increased DNA damage induced by ROS-induced NOX and NADPH oxidase [138]. Several studies demonstrated that oxidative stress facilitates EBV-induced B-cell transformation through posttranscriptional regulation of viral ( LMP1 ) and host ( STAT3 ) genes, which are critical for promoting B-cell immortalisation, malignant transformation, and tumorigenesis [132, 138, 139]. IFI16 inflammasome with adaptor ASC protein was shown to be activated upon sensing of latent EBV infection in all types of latency, and this leads to induction of IL-1 β , IL-18, and IL-33 maturation [140].…”

“…Although EBV is not integrated into host genome, its materials such as EBNA1 and BZLF1 seem to interact with various cellular promoters and induce epigenetic alterations. Epigenetic regulation of viral and host cellular growth-promoting factors such as EBNA1, BZLF1, STAT3, XIAP-associated factor 1 (XAF1), and DNA inducible factor 45 alpha (GADD45 α ) induces oxidative stress and expedites EBV-induced B-cell transformation [132, 138, 139, 144]. EBV-induced elevated level of ROS promotes excessive production of receptor activator of NF- κ B ligand (RANKL) that interacts with RANK receptor in the periapical area leading to bone resorption and apical periodontitis [145].…”