Tannic acid potently inhibits tumor cell proteasome activity, increases p27 and Bax expression, and induces G1 arrest and apoptosis.
Animal studies have demonstrated that a dietary polyphenol known as tannic acid (TA) exhibits anticarcinogenic activity in chemically induced cancers, although the involved molecular target remains unknown. In addition, proteasome inhibitors have been shown to suppress human tumor growth in nude mice. Most recently, we have reported that ester-bond-containing tea polyphenols are potent proteasome inhibitors in vitro and in vivo. We have hypothesized that TA, which contains multiple similar gallate moieties linked by ester bonds, should inhibit the proteasome activity. Here, we report that indeed TA potently and specifically inhibits the chymotrypsin-like activity of purified 20S proteasome (IC(50) = 0.06 microg/ml), 26S proteasome of Jurkat T-cell extracts, and 26S proteasome of living Jurkat cells. Inhibition of the proteasome by TA in Jurkat cells results in accumulation of two natural proteasome substrates, the cyclin-dependent kinase inhibitor p27(Kip1) and the proapoptotic protein Bax, followed by growth arrest in G1 and induction of apoptotic cell death. Our present study suggests that TA targets and inhibits the proteasome in tumor cells, which may contribute to the previously observed anticarcinogenic activity of TA.
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Drug Discovery Program, H. Lee Moffitt Cancer Center & Research Institute, and Interdisciplinary Oncology Program and Department of Biochemistry & Molecular Biology, College of Medicine, University of South Florida, Tampa, Florida 33612, USA.
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D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D018844:Cyclin-Dependent Kinases; D003546:Cysteine Endopeptidases / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D016193:G1 Phase / Q000187:drug effects*; D006801:Humans; D047348:Hydrolyzable Tannins / Q000494:pharmacology*; D019169:Jurkat Cells / Q000187:drug effects / Q000378:metabolism; D008840:Microfilament Proteins / Q000187:drug effects*; D009097:Multienzyme Complexes / Q000187:drug effects* / Q000378:metabolism; D009124:Muscle Proteins; D046988:Proteasome Endopeptidase Complex; D011518:Proto-Oncogene Proteins / Q000187:drug effects*; D019253:Proto-Oncogene Proteins c-bcl-2; D012016:Reference Values; D012680:Sensitivity and Specificity; D014407:Tumor Cells, Cultured; D051028:bcl-2-Associated X Protein
C494826:BAX protein, human; D047348:Hydrolyzable Tannins; D008840:Microfilament Proteins; D009097:Multienzyme Complexes; D009124:Muscle Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C058992:Tagln protein, mouse; D051028:bcl-2-Associated X Protein; D018844:Cyclin-Dependent Kinases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex