Berberine induces autophagic cell death and mitochondrial apoptosis in liver cancer cells: the cellular mechanism.
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.
Wang
Ning
N
School of Chinese Medicine, The University of Hong Kong, 10 Sassoon Road, Pokfulam, Hong Kong, PR of China.
Feng
Yibin
Y
Zhu
Meifen
M
Tsang
Chi-Man
CM
Man
Kwan
K
Tong
Yao
Y
Tsao
Sai-Wah
SW
D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects / Q000235:genetics; D000071186:Beclin-1; D001599:Berberine / Q000494:pharmacology* / Q000627:therapeutic use; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects*; D045304:Cytochromes c / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D015151:Immunoblotting; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008565:Membrane Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D034622:RNA Interference; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D008565:Membrane Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D001599:Berberine; D045304:Cytochromes c; D048051:p38 Mitogen-Activated Protein Kinases