Ester bond-containing tea polyphenols potently inhibit proteasome activity in vitro and in vivo.
It has been discovered that proteasome inhibitors are able to induce tumor growth arrest or cell death and that tea consumption is correlated with cancer prevention. Here, we show that ester bond-containing tea polyphenols, such as (-)-epigallocatechin-3-gallate (EGCG), potently and specifically inhibit the chymotrypsin-like activity of the proteasome in vitro (IC(50) = 86-194 nm) and in vivo (1-10 microm) at the concentrations found in the serum of green tea drinkers. Atomic orbital energy analyses and high performance liquid chromatography suggest that the carbon of the polyphenol ester bond is essential for targeting, thereby inhibiting the proteasome in cancer cells. This inhibition of the proteasome by EGCG in several tumor and transformed cell lines results in the accumulation of two natural proteasome substrates, p27(Kip1) and IkappaB-alpha, an inhibitor of transcription factor NF-kappaB, followed by growth arrest in the G(1) phase of the cell cycle. Furthermore, compared with their simian virus-transformed counterpart, the parental normal human fibroblasts were much more resistant to EGCG-induced p27(Kip1) protein accumulation and G(1) arrest. Our study suggests that the proteasome is a cancer-related molecular target of tea polyphenols and that inhibition of the proteasome activity by ester bond-containing polyphenols may contribute to the cancer-preventative effect of tea.
Drug Discovery Program, H. Lee Moffitt Cancer Center and Research Institute and Interdisciplinary Oncology Program and Department of Biochemistry and Molecular Biology, University of South Florida College of Medicine, Tampa, Florida 33612, USA.
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D002154:Calpain / Q000378:metabolism; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002392:Catechin / Q000031:analogs & derivatives / Q000494:pharmacology*; D018797:Cell Cycle Proteins; D002461:Cell Line, Transformed; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004952:Esters / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D005347:Fibroblasts; D005419:Flavonoids; D006801:Humans; D020672:I-kappa B Proteins; D019169:Jurkat Cells; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008958:Models, Molecular; D008968:Molecular Conformation; D009097:Multienzyme Complexes / Q000378:metabolism*; D000072000:NF-KappaB Inhibitor alpha; D010636:Phenols / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D011108:Polymers / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D011471:Prostatic Neoplasms; D046988:Proteasome Endopeptidase Complex; D013329:Structure-Activity Relationship; D013662:Tea / Q000737:chemistry*; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
D018797:Cell Cycle Proteins; D015853:Cysteine Proteinase Inhibitors; D004268:DNA-Binding Proteins; D004952:Esters; D005419:Flavonoids; D020672:I-kappa B Proteins; D008869:Microtubule-Associated Proteins; D009097:Multienzyme Complexes; C000606204:NFKBIA protein, human; D010636:Phenols; D011108:Polymers; D013662:Tea; D025521:Tumor Suppressor Proteins; D000072000:NF-KappaB Inhibitor alpha; D050760:Cyclin-Dependent Kinase Inhibitor p27; D002392:Catechin; C045651:epigallocatechin gallate; D018844:Cyclin-Dependent Kinases; C505407:CASP3 protein, human; D002154:Calpain; D053148:Caspase 3; D020169:Caspases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex