Dietary flavonoids as proteasome inhibitors and apoptosis inducers in human leukemia cells
Dietary flavonoids as proteasome inhibitors and apoptosis inducers in human leukemia cells
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DOI：
10.1016/j.bcp.2005.02.022
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发表时间：
2005-05-15
影响因子：
5.8
通讯作者：
Dou, QP
中科院分区：
文献类型：
--
作者：
Chen, D;Daniel, KG;Dou, QP
研究表明，蛋白酶体活性是癌细胞存活所必需的，水果和蔬菜的消费与癌症风险降低有关。以前，我们报道葡萄提取物可以抑制蛋白酶体活性并诱导肿瘤细胞凋亡。在这项研究中，我们研究了黄酮类化合物芹菜素，槲皮素，山奈酚和杨梅素的蛋白酶体抑制和诱导肿瘤细胞凋亡的能力。我们报道芹菜素和槲皮素比山奈酚和杨梅素更有效：（i）抑制完整白血病Jurkat T细胞中纯化的20 S蛋白酶体和26 S蛋白酶体的糜蛋白酶样活性;（ii）积累两种蛋白酶体靶蛋白的推定泛素化形式，Bax和核因子κ β-α的抑制剂和（iii）诱导Jurkat T细胞中半胱天冬酶-3的活化和聚（ADP-核糖）聚合酶的裂解。这些化合物的蛋白酶体抑制能力与它们的促凋亡能力相关。这些黄酮类化合物的蛋白酶体的胰凝乳蛋白酶位点（β 5亚基）的潜在相互作用的计算建模的结果与所获得的蛋白酶体抑制活性是一致的。我们发现C-4碳可能是蛋白酶体β 5亚基N端苏氨酸的OH基团的亲核攻击位点，C-3羟基可能改变这些黄酮类化合物抑制蛋白酶体的能力。最后，芹菜素既不能有效地抑制蛋白酶体活性，也不能诱导非转化的人自然杀伤细胞凋亡。我们的研究结果表明，蛋白酶体可能是这些膳食黄酮类化合物在人类肿瘤细胞中的靶点，黄酮类化合物对蛋白酶体的抑制可能是其预防癌症作用的机制之一。(c)2005年爱思唯尔公司All rights reserved.
It has been shown that proteasome activity is required for cancer cell survival and consumption of fruits and vegetables is associated with decreased cancer risk. Previously, we reported that grape extract could inhibit proteasome activity and induce apoptosis in tumor cells. In this study, we examined the flavonoids apigenin, quercetin, kaempferol and myricetin for their proteasome-inhibitory and apoptosis-inducing abilities in human tumor cells. We report that apigenin and quercetin are much more potent than kaempferol and myricetin at: (i) inhibiting chymotrypsin-like activity of purified 20S proteasome and of 26S proteasome in intact leukemia Jurkat T cells; (ii) accumulating putative ubiquitinated forms of two proteasome target proteins, Bax and Inhibitor of nuclear factor kappa beta-alpha in Jurkat T cells and (iii) inducing activation of caspase-3 and cleavage of poly(ADP-ribose) polymerase in Jurkat T cells. The proteasome-inhibitory abilities of these compounds correlated with their apoptosis-inducing potencies. Results from computational modeling of the potential interactions of these flavonoids to the chymotrypsin site (beta 5 subunit) of the proteasome were consistent with the obtained proteasome-inhibitory activities. We found that the C-4 carbon may be a site of nucleophilic attack by the OH group of N-terminal threonine of proteasomal beta 5 subunit and that the C-3 hydroxyl may alter the ability of these flavonoids to inhibit the proteasome. Finally, apigenin neither effectively inhibited the proteasome activity nor induced apoptosis in non-transformed human natural killer cells. Our results suggested that the proteasome may be a target of these dietary flavonoids in human tumor cells and that inhibition of the proteasome by flavonoids may be one of the mechanisms responsible for their cancer-preventive effects. (c) 2005 Elsevier Inc. All rights reserved.