Ester Bond-containing Tea Polyphenols Potently Inhibit Proteasome Activity in Vitro and in Vivo

Nam, Sangkil; Smith, David M.; Dou, Q. Ping

doi:10.1074/jbc.m004209200

Cited by 479 publications

(468 citation statements)

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“…Other mechanisms are possible, including effects on proinflammatory signalling pathways. For instance, it has been reported that EGCG inhibits the chymotrypsin-like activity of the proteasome, with IC 50 values in the range 86-194 nM, and subsequent accumulation of IjB-a [55]. This would result in inhibition of NF-jB activation and in downstream inhibition of NF-jB-regulated genes such as the matrixins [56,57].…”

Section: Discussionmentioning

confidence: 99%

Selective inhibition of ADAMTS‐1, ‐4 and ‐5 by catechin gallate esters

Vankemmelbeke

Jones

Fowles

et al. 2003

European Journal of Biochemistry

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Three mammalian ADAMTS enzymes, ADAMTS-1, -4 and -5, are known to cleave aggrecan at certain glutamyl bonds and are considered to be largely responsible for cartilage aggrecan catabolism observed during the development of arthritis. We have previously reported that certain catechins, polyphenolic compounds found in highest concentration in green tea (Camellia sinensis), are capable of inhibiting cartilage aggrecan breakdown in an in vitro model of cartilage degradation. We have now cloned and expressed recombinant human ADAMTS-1, -4 and -5 and report here that the catechin gallate esters found in green tea potently inhibit the aggrecan-degrading activity of these enzymes, with submicromolar IC 50 values. Moreover, the concentration needed for total inhibition of these members of the ADAMTS group is approximately two orders of magnitude lower than that which is needed to partially inhibit collagenase or ADAM-10 activity. Catechin gallate esters therefore provide selective inhibition of certain members of the ADAMTS group of enzymes and could constitute an important nutritional aid in the prevention of arthritis as well as being part of an effective therapy in the treatment of joint disease and other pathologies involving the action of these enzymes.Keywords: ADAMTS; enzyme inhibition; catechin; gallate; aggrecanase.Green tea, made from the leaves of Camellia sinensis, contains catechins, a group of polyphenolic compounds with antioxidant properties that have been at the centre of investigations into the potential medical benefits of consuming green tea. The most abundant catechin in green tea is (-)-epigallocatechin gallate (EGCG) with others such as (-)-epicatechin (EC), (-)-epigallocatechin (EGC) and (-)-epicatechin gallate (ECG) also present. Anti-inflammatory and anti-mitotic properties have been attributed to these compounds [1-3] and they have also been reported to inhibit certain matrixins such as the gelatinases [4][5][6]. The beneficial effects on a range of clinical conditions including cancer growth and metastasis [7][8][9][10][11], cardiovascular and liver diseases [12] may therefore be due to one or a combination of these properties.Aggrecan, a large aggregating proteoglycan, is together with type II collagen the major constituent of articular cartilage. Degradation of cartilage aggrecan has mainly been attributed to the action of glutamyl endopeptidases, termed ÔaggrecanasesÕ. Aggrecan degradation products resulting from aggrecanase action have been found in in vitro cultures of cartilage treated with proinflammatory cytokines as well as in synovial fluid of arthritis patients [13][14][15][16]. To date three mammalian ÔaggrecanasesÕ have been identified: a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-1, -4 and -5 [17][18][19]. The ADAMTS enzymes belong to a subgroup of metallopeptidases in Family M12 of Clan MA in the Merops database [20] and are related to the ADAMs and matrixins [21]. So far, at least 18 mammalian ADAMTS enzymes have been identified, most of which remain t...

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Section: Discussionmentioning

confidence: 99%

Selective inhibition of ADAMTS‐1, ‐4 and ‐5 by catechin gallate esters

Vankemmelbeke

Jones

Fowles

et al. 2003

European Journal of Biochemistry

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“…This point is illustrated in the inhibition of 20 s proteasome chymotryptic activities by EGCG; i.e. the IC 50 observed in a cell-free system was 0.1-0.2 μM, but it was 1-40 μM in tumor cell lines [54]. EGCG was reported to bind to the 67-kDa laminin receptor with a K d of 0.04 μM, to vimentin with a K d of 3.3 nM, and interact with Bcl-2 with a K i of 0.33 μM [50][51][52].…”

Section: Mechanistic Studies On the Activities Of Egcg In Cell Linesmentioning

confidence: 99%

Inhibition of carcinogenesis by tea constituents

Lǚ

Lambert

et al. 2007

Seminars in Cancer Biology

130

104

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The possible cancer preventive activity of tea has received much attention in recent years. The inhibitory activities of tea and tea constituents against carcinogenesis at different organ sites have been demonstrated in many animal models. The effect of tea consumption on human cancers, however, remains inconclusive. The mechanisms of action of tea polyphenols, especially EGCG, the most abundant and active catechin, have been extensively investigated. Most of the studies, however, were based on cell culture systems, and these mechanisms need to be evaluated and verified in animal models or humans in order to gain more understanding on the effect of tea consumption on human cancer. Human intervention trials are warranted to determine the possible prevention of cancer of specific sites by preparation of tea constituents.

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“…(Ϫ)Epigallocatechin-3-gallate (EGCG) is the major bioactive polyphenol present in green tea. It possesses anti-oxidant (16), anti-mutagenic (17), anti-proteolytic (18,19), and anti-proliferative activity (20). In addition, it has been shown to increase p27 KIP-1 levels, inhibit cyclin activity, and inhibit cell cycle progression (21,22).…”

mentioning

confidence: 99%

Epigallocatechin-3-gallate Inhibits Epidermal Growth Factor Receptor Signaling Pathway

Sah

Balasubramanian

Eckert

et al. 2004

Journal of Biological Chemistry

238

143

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Epidermal growth factor receptor (EGFR) activation is absolutely required for cervical cell proliferation. This suggests that EGFR-inhibitory agents may be of therapeutic value. In the present study, we investigated the effects of epigallocatechin-3-gallate (EGCG), a bioactive green tea polyphenol, on EGFR signaling in cervical cells. EGCG inhibits epidermal growth factor-dependent activation of EGFR, and EGFR-dependent activation of the mitogen-activated protein kinases ERK1/2. EGCG also inhibits EGFR-dependent AKT activity. The EGCGdependent reduction in ERK and AKT activity is associated with reduced phosphorylation of downstream substrates, including p90RSK, FKHR, and BAD. These changes are associated with increased p53, p21 WAF-1 , and p27 KIP-1 levels, reduced cyclin E level, and reduced CDK2 kinase activity. Consistent with these findings, flow cytometry and TUNEL (terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling) staining revealed EGCG-dependent G 1 arrest. Moreover, sustained EGCG treatment caused apoptotic cell death. In addition to inhibiting EGFR, cell-free studies demonstrated that EGCG directly inhibits ERK1/2 and AKT, suggesting that EGCG acts simultaneously at multiple levels to inhibit EGF-dependent signaling. Importantly, the EGCG inhibition is selective, as EGCG does not effect the EGFR-dependent activation of JNK. These results suggest that EGCG acts to selectively inhibit multiple EGF-dependent kinases to inhibit cell proliferation.

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Ester Bond-containing Tea Polyphenols Potently Inhibit Proteasome Activity in Vitro and in Vivo

Cited by 479 publications

References 38 publications

Selective inhibition of ADAMTS‐1, ‐4 and ‐5 by catechin gallate esters

Selective inhibition of ADAMTS‐1, ‐4 and ‐5 by catechin gallate esters

Inhibition of carcinogenesis by tea constituents

Epigallocatechin-3-gallate Inhibits Epidermal Growth Factor Receptor Signaling Pathway

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