Degradation of MDM2 by the interaction between berberine and DAXX leads to potent apoptosis in MDM2-overexpressing cancer cells

• Authors: Xiaoling Zhang, Emory University; Lubing Gu, Emory University; Jiansha Li, Emory University; Noopur Shah, Emory University; Jing He, Emory University; Lin Yang, Emory University; Qun Hu, Tongji Hospital; Muxiang Zhou, Emory University
• Journal Title: Cancer Research
• Volume: Volume 70, Number 23
• Publisher: American Association for Cancer Research | 2010-12-01, Pages 9895-9904
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1158/0008-5472.CAN-10-1546
• Subjects: Health Sciences, Oncology
• Keywords: MDM2; DAXX; Berberine; Cancer; Apoptosis

Abstract

Berberine, a natural product derived from a plant used in Chinese herbal medicine, is reported to exhibit anticancer effects; however, its mechanism of action is not clearly defined. Herein, we demonstrate that berberine induces apoptosis in acute lymphoblastic leukemia (ALL) cells by downregulating the MDM2 oncoprotein. The pro-apoptotic effects of berberine were closely associated with both the MDM2 expression levels and p53 status of a set of ALL cell lines. The most potent apoptosis was induced by berberine in ALL cells with both MDM2 overexpression and a wild-type (wt) p53, while no pro-apoptotic effect was detected in ALL cells that were negative for MDM2 and wt-p53. In contrast to the conventional chemotherapeutic drug doxorubicin, which induces p53 activation and a subsequent upregulation of MDM2, berberine strongly induced persistent downregulation of MDM2 followed by a steady-state activation of p53. We discovered that downregulation of MDM2 in ALL cells by berberine occurred at a post-translational level through modulation of DAXX, which disrupted the MDM2-DAXX-HAUSP interactions and thereby promoted MDM2 self-ubiquitination and degradation. Given that MDM2-overexpressing cancer cells are commonly chemoresistant, our findings suggest that this naturally-derived agent may have a highly useful role in the treatment of cancer patients with refractory disease.