Ester bond-containing tea polyphenols potently inhibit proteasome activity in vitro and in vivo
Ester bond-containing tea polyphenols potently inhibit proteasome activity in vitro and in vivo
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DOI：
10.1074/jbc.m004209200
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发表时间：
2001-04-20
影响因子：
4.8
通讯作者：
Dou, QP
中科院分区：
文献类型：
--
作者：
Nam, S;Smith, DM;Dou, QP
已经发现蛋白酶体抑制剂能够诱导肿瘤生长停滞或细胞死亡，并且喝茶与癌症预防相关。在这里，我们表明，含酯键的茶多酚，如（-）-表没食子儿茶素-3-没食子酸酯（EGCG），在体外（IC 50 = 86-194 nM）和体内（1-10 μ M）在绿色茶饮用者血清中发现的浓度下，有效地和特异性地抑制胰凝乳蛋白酶样活性的蛋白酶体。原子轨道能量分析和高效液相色谱表明，多酚酯键的碳对于靶向是必不可少的，从而抑制癌细胞中的蛋白酶体。在几种肿瘤和转化细胞系中，EGCG对蛋白酶体的这种抑制导致两种天然蛋白酶体底物p27（Kip 1）和I κ B-α（转录因子NF-κ B的抑制剂）的积累，随后在细胞周期的G1期生长停滞。此外，与它们的猴病毒转化的对应物相比，亲本正常人成纤维细胞对EGCG诱导的p27（Kip 1）蛋白积累和G（1）阻滞的抵抗力更强。我们的研究表明，蛋白酶体是茶多酚的癌症相关的分子靶点，含有酯键的多酚抑制蛋白酶体活性可能有助于茶叶的癌症预防作用。
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 (IC50 = 86-194 nM) and in vivo (1-10 muM) 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 I kappaB-alpha, an inhibitor of transcription factor NF-kappaB, followed by growth arrest in the G, 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.