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      Proteomic identification of molecular targets of gambogic acid: role of stathmin in hepatocellular carcinoma.

      Proteomics

      pharmacology, Blotting, Western, Carcinoma, Hepatocellular, metabolism, Cell Line, Tumor, Cell Proliferation, drug effects, Cyclin-Dependent Kinase 4, antagonists & inhibitors, GTP-Binding Protein beta Subunits, Gene Expression, Humans, Inhibitory Concentration 50, Proteomics, RNA, Small Interfering, Stathmin, genetics, Xanthones

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          Abstract

          Gamboge has been developed as an injectable drug for cancer treatment in China. In this study, the inhibition ratio and their IC(50) values of two derivatives from Gamboge in hepatocellular carcinoma (HCC) were determined. Proteomic approach was employed to reveal the target proteins of these two derivatives, gambogic acid (GA), and gambogenic acid (GEA). HCC cells were cultured under varied conditions with the addition of either GA or GEA. Twenty differentially expressed proteins were identified and the four most distinctly expressed proteins were further validated by Western blotting. GA and GEA revealed inhibitory effects on HCC cell proliferation. The expression of cyclin-dependent kinase 4 inhibitor A and guanine nucleotide-binding protein beta subunit 1 were upregulated by both xanthones, whilst the expression of 14-3-3 protein sigma and stathmin 1 (STMN1) were downregulated. Furthermore, overexpression of STMN1 in HCC cells decreased their sensitivity, whilst small interfering RNAs targeting STMN1 enhanced their sensitivity to GA and GEA. In conclusion, our study suggested for the first time that STMN1 might be a major target for GA and GEA in combating HCC. Further investigation may lead to a new generation of anticancer drugs exerting synergistic effect with conventional therapy, thus to promote treatment efficacy.

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          Journal
          10.1002/pmic.200800155
          19086098

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