Journal
JOURNAL OF CELLULAR BIOCHEMISTRY
Volume 111, Issue 6, Pages 1426-1436Publisher
WILEY
DOI: 10.1002/jcb.22869
Keywords
BERBERINE; AUTOPHAGY; APOPTOSIS; BCL-2/BECLIN-1; MTOR
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Funding
- Research Council of the University of Hong Kong [200811159197, 200907176140]
- Research Grants Council of Hong Kong [HKU764708M]
- Pong Ding Yueng Endowment Fund for Education & Research in Chinese-Western Medicine [20005274]
- Hong Kong Government [20740314]
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Extensive studies have revealed that berberine, a small molecule derived from Coptidis rhizoma (Huanglian in Chinese) and many other plants, has strong anti-tumor properties. To better understand berberine-induced cell death and its underlying mechanisms in cancer, we examined autophagy and apoptosis in the human hepatic carcinoma cell lines HepG2 and MHCC97-L. The results of this study indicate that berberine can induce both autophagy and apoptosis in hepatocellular carcinoma cells. Berberine-induced cell death in human hepatic carcinoma cells was diminished in the presence of the cell death inhibitor 3-methyladenine, or following interference with the essential autophagy gene Atg5. Mechanistic studies showed that berberine may activate mitochondrial apoptosis in HepG2 and MHCC97-L cells by increasing Bax expression, the formation of permeable transition pores, cytochrome C release to cytosol, and subsequent activation of the caspases 3 and 9 execution pathway. Berberine may also induce autophagic cell death in HepG2 and MHCC97-L cells through activation of Beclin-1 and inhibition of the mTOR-signaling pathway by suppressing the activity of Akt and up-regulating P38 MAPK signaling. This is the first study to describe the role of Beclin-1 activation and mTOR inhibition in berberine-induced autophagic cell death. These results further demonstrate the potential of berberine as a therapeutic agent in the emerging list of cancer therapies with novel mechanisms. J. Cell. Biochem. 111: 1426-1436, 2010. (C) 2010 Wiley-Liss, Inc.
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