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

Li D, Lu Y, Sun P, Feng LX, Liu M, Hu LH, Wu WY, Jiang BH, Yang M, Qu XB, Guo DA, Liu X - PLoS ONE (2015)

Bottom Line: Moore.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.

View Article: PubMed Central - PubMed

Affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P.R. China; Changchun University of Chinese Medicine, Changchun 130117, P.R. China.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus

Over-expression of proteasome β1 subunit increased sensitivity of cells to cytotoxicity of fangchinoline.(A) Results of Western blotting assay of proteasome β1 subunit protein expression in wild-type cells, negative-control cells and cells transfected with plasmid encoding PSMB6. (B) Cell viability of wild-type cells, negative-control cells and cells transfected with plasmid encoding PSMB6 after 24 h treatment of fangchinoline at different concentrations. (C) Cell viability of wild type cells, negative control cells and cells transfected with plasmid encoding PSMB6 after 48 h fangchinoline treatment. (d) Cell viability of wild type cells, negative control cells and cells transfected with plasmid encoding PSMB6 after 72 h fangchinoline treatment. Data were statistical results of three independent experiments.
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pone.0141681.g007: Over-expression of proteasome β1 subunit increased sensitivity of cells to cytotoxicity of fangchinoline.(A) Results of Western blotting assay of proteasome β1 subunit protein expression in wild-type cells, negative-control cells and cells transfected with plasmid encoding PSMB6. (B) Cell viability of wild-type cells, negative-control cells and cells transfected with plasmid encoding PSMB6 after 24 h treatment of fangchinoline at different concentrations. (C) Cell viability of wild type cells, negative control cells and cells transfected with plasmid encoding PSMB6 after 48 h fangchinoline treatment. (d) Cell viability of wild type cells, negative control cells and cells transfected with plasmid encoding PSMB6 after 72 h fangchinoline treatment. Data were statistical results of three independent experiments.

Mentions: As shown in Fig 7A, transfection of plasmid encoding proteasome subunit beta type 6 (PSMB6) cDNA caused over-expression of proteasome β1 subunit in PC-3 cells. Results of MTT assay of the inhibitive effects of fangchinoline on proliferation of wild type, negative control and PSMB6-transfected cells showed that cells with over-expression of proteasome β1 subunit were more sensitive to cytotoxictiy of fangchinoline treatment for 24 h (Fig 7B), 48 h (Fig 7C) or 72 h (Fig 7D).


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

Li D, Lu Y, Sun P, Feng LX, Liu M, Hu LH, Wu WY, Jiang BH, Yang M, Qu XB, Guo DA, Liu X - PLoS ONE (2015)

Over-expression of proteasome β1 subunit increased sensitivity of cells to cytotoxicity of fangchinoline.(A) Results of Western blotting assay of proteasome β1 subunit protein expression in wild-type cells, negative-control cells and cells transfected with plasmid encoding PSMB6. (B) Cell viability of wild-type cells, negative-control cells and cells transfected with plasmid encoding PSMB6 after 24 h treatment of fangchinoline at different concentrations. (C) Cell viability of wild type cells, negative control cells and cells transfected with plasmid encoding PSMB6 after 48 h fangchinoline treatment. (d) Cell viability of wild type cells, negative control cells and cells transfected with plasmid encoding PSMB6 after 72 h fangchinoline treatment. Data were statistical results of three independent experiments.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4626104&req=5

pone.0141681.g007: Over-expression of proteasome β1 subunit increased sensitivity of cells to cytotoxicity of fangchinoline.(A) Results of Western blotting assay of proteasome β1 subunit protein expression in wild-type cells, negative-control cells and cells transfected with plasmid encoding PSMB6. (B) Cell viability of wild-type cells, negative-control cells and cells transfected with plasmid encoding PSMB6 after 24 h treatment of fangchinoline at different concentrations. (C) Cell viability of wild type cells, negative control cells and cells transfected with plasmid encoding PSMB6 after 48 h fangchinoline treatment. (d) Cell viability of wild type cells, negative control cells and cells transfected with plasmid encoding PSMB6 after 72 h fangchinoline treatment. Data were statistical results of three independent experiments.
Mentions: As shown in Fig 7A, transfection of plasmid encoding proteasome subunit beta type 6 (PSMB6) cDNA caused over-expression of proteasome β1 subunit in PC-3 cells. Results of MTT assay of the inhibitive effects of fangchinoline on proliferation of wild type, negative control and PSMB6-transfected cells showed that cells with over-expression of proteasome β1 subunit were more sensitive to cytotoxictiy of fangchinoline treatment for 24 h (Fig 7B), 48 h (Fig 7C) or 72 h (Fig 7D).

Bottom Line: Moore.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.

View Article: PubMed Central - PubMed

Affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P.R. China; Changchun University of Chinese Medicine, Changchun 130117, P.R. China.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus