Inhibition on Proteasome β1 Subunit Might Contribute to the Anti-Cancer Effects of Fangchinoline in Human Prostate Cancer Cells

• Published in: PloS one Vol. 10; no. 10; p. e0141681
• Main Authors: Li, Dong, Lu, Yu, Sun, Peng, Feng, Li-Xing, Liu, Miao, Hu, Li-Hong, Wu, Wan-Ying, Jiang, Bao-Hong, Yang, Min, Qu, Xiao-Bo, Guo, De-An, Liu, Xuan
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 29.10.2015; Public Library of Science (PLoS)
• Subjects: Animals; Anticancer properties; Antineoplastic Agents, Phytogenic - pharmacology; Apoptosis; Apoptosis - drug effects; Autophagy; BAX protein; bcl-2-Associated X Protein - metabolism; Benzylisoquinolines - pharmacology; Bisbenzylisoquinoline; Cancer; Cancer therapies; Caspase; Catalytic Domain; Cell cycle; Cell Cycle Checkpoints - drug effects; Cell Line, Tumor; Cell proliferation; Cell Proliferation - drug effects; Chinese medicine; Cyclin-Dependent Kinase Inhibitor p27 - metabolism; Cytokines; Cytotoxicity; Disease Models, Animal; Enzyme Activation; Enzymes; Erythrocytes; G1 phase; Gene Expression; Gene Knockdown Techniques; Humans; I-kappa B Proteins - metabolism; Inflammatory diseases; Inhibition; Male; Mice; Mouse devices; Overexpression; Penicillin; Prostate cancer; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Proteasome Endopeptidase Complex - chemistry; Proteasome Endopeptidase Complex - genetics; Proteasome Endopeptidase Complex - metabolism; Proteasome inhibitors; Proteasome Inhibitors - pharmacology; Protein Binding; Protein Subunits - antagonists & inhibitors; Proteins; Recombinant Proteins; Substrates; Tetrandrine; Toxicity; Traditional Chinese medicine; Transfection; Tumors; Ubiquitination; Xenograft Model Antitumor Assays; Xenografts; Xenotransplantation; China
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0141681

Fangchinoline is a bisbenzylisoquinoline alkaloid isolated from Radix Stephaniae tetrandrae S. Moore. Fangchinoline and its structure analogue, tetrandrine, exhibited direct binding affinity with recombinant human proteasome β1 subunit and also inhibited its activity in vitro. In cultured prostate PC-3 cells and LnCap cells, fangchinoline could dose-dependently inhibit cell proliferation and caspase-like activity of cellular proteasome which was mediated by proteasome β1 subunit. The inhibitive effect of fangchinoline on caspase-like activity of proteasome was also observed in purified human erythrocyte 20S proteasome. In PC-3 cells, fangchinoline induced cell cycle arrest at G0/G1 phase and apoptosis. Treatment of PC-3 tumor-bearing nude mice with fangchinoline inhibited tumor growth, induced apoptosis and also caused decrease in proteasome activities in tumor xenografts. Dose-dependent and time-dependent accumulation of ubiquitinated proteins and important proteasome substrates such as p27, Bax and IκB-α were observed in fangchinoline-treated cells. Over-expression of proteasome β1 subunit by plasmid transfection increased sensitivity of cells to the cytotoxicity of fangchinoline while knockdown of proteasome β1 subunit ameliorated cytotoxicity of fangchinoline in PC-3 cells. Results of the present study suggested that proteasome inhibition was involved in the anti-cancer effects of fangchinoline. Fangchinoline and its structure analogues might be new natural proteasome inhibitors targeting β1 subunit.