Blocking autophagy enhances the apoptosis effect of bufalin on human hepatocellular carcinoma cells through endoplasmic reticulum stress and JNK activation

• Published in: Apoptosis (London) 2014-01, Vol.19 (1), p.210-223
• Main Authors: Hu, Fengli, Han, Jiwu, Zhai, Bo, Ming, Xiaodong, Zhuang, Liwei, Liu, Yong, Pan, Shangha, Liu, Tiefu
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents, Phytogenic - pharmacology; Apoptosis - drug effects; Autophagy - drug effects; Biochemistry; Biomedical and Life Sciences; Biomedicine; Bufanolides - pharmacology; Cancer Research; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - enzymology; Carcinoma, Hepatocellular - physiopathology; Cell Biology; Cell Line, Tumor; Cell Survival - drug effects; Down-Regulation - drug effects; Drugs, Chinese Herbal - pharmacology; Endoplasmic Reticulum Stress - drug effects; Enzyme Activation - drug effects; Herbal medicine; Humans; Liver Neoplasms - drug therapy; Liver Neoplasms - enzymology; Liver Neoplasms - physiopathology; MAP Kinase Kinase 4 - genetics; MAP Kinase Kinase 4 - metabolism; Oncology; Original Paper; Up-Regulation - drug effects; Virology
• ISSN: 1360-8185; 1573-675X
• DOI: 10.1007/s10495-013-0914-7

Bufalin extracts are a part of traditional Chinese medicine, Chansu. In the current study, we investigated the effect of bufalin on the proliferation of the human hepatocellular carcinoma (HCC) cell lines, Huh-7 and HepG-2, and explored the therapeutic potential of the drug. Our results demonstrated that bufalin markedly inhibited cell proliferation and promoted apoptosis in the Huh-7 and HepG-2 cells in vitro. The underlying mechanism of the bufalin-induced apoptosis was the induction of endoplasmic reticulum (ER) stress via the IRE1–JNK pathway. In addition, during the ER stress response, the autophagy pathway, characterized by the conversion of LC3-I to LC3-II, was activated, resulting in increased Beclin-1 protein levels, decreased p62 expression and stimulation of autophagic flux. Our data supported the pro-survival role of bufalin-induced autophagy when the autophagy pathway was blocked with specific chemical inhibitors; the involvement of the IRE1 pathway in the ER stress-induced autophagy was also demonstrated when the expression of IRE1 and CHOP was silenced using siRNA. These data indicate that combining bufalin with a specific autophagy inhibitor could be a promising therapeutic approach for the treatment of HCC.