Inducing apoptosis of cancer cells using small-molecule plant compounds that bind to GRP78.
Inducing apoptosis of cancer cells using small-molecule plant compounds that bind to GRP78.
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DOI：
10.1038/bjc.2013.325
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发表时间：
2013-07-23
影响因子：
8.8
通讯作者：
Redfern CP
中科院分区：
文献类型：
--
作者：
Martin S;Lamb HK;Brady C;Lefkove B;Bonner MY;Thompson P;Lovat PE;Arbiser JL;Hawkins AR;Redfern CP
葡萄糖调节蛋白78（GRP 78）是内质网（ER）应激的感受器。本研究的目的是检验结合GRP 78的分子与ER应激诱导剂组合诱导未折叠蛋白反应（UPR）并增强细胞死亡的假设。差示扫描量热法（DSC），通过流式细胞术测量细胞死亡，并使用蛋白质印迹法诱导ER应激标志物。表没食子儿茶素没食子酸酯（Epigallocatechin gallate，EGCG）是绿色茶（Camellia sinensis）中的黄酮类化合物，和厚朴（honoklavin，HNK）是广花木兰（Magnolia grandiflora）的衍生物，它们与GRP 78 ATP酶结构域的未折叠构象结合。表没食子儿茶素没食子酸酯和HNK诱导六个神经外胚层肿瘤细胞系测试死亡。HNK的死亡水平是EGCG的两倍;半最大有效剂量相似，但EGCG的敏感性在细胞类型之间变化更大。和厚朴素诱导ER应激和UPR，如其与GRP 78相互作用的能力所预测的，但EGCG效果较差。在细胞死亡方面，HNK与ER应激诱导剂芬维A胺或硼替佐米对黑色素瘤和胶质母细胞瘤细胞具有协同作用，但对神经母细胞瘤细胞仅具有累加（芬维A胺）或抑制（硼替佐米）作用。和厚朴素通过与GRP 78的相互作用诱导ER应激引起的细胞凋亡。数据与DSC结果一致，表明HNK比EGCG更有效地结合GRP 78。因此，HNK可能值得开发为抗肿瘤药物。
Glucose regulated protein 78 (GRP78) functions as a sensor of endoplasmic reticulum (ER) stress. The aim of this study was to test the hypothesis that molecules that bind to GRP78 induce the unfolded protein response (UPR) and enhance cell death in combination with ER stress inducers. Differential scanning calorimetry (DSC), measurement of cell death by flow cytometry and the induction of ER stress markers using western blotting. Epigallocatechin gallate (EGCG), a flavonoid component of Green Tea Camellia sinensis, and honokiol (HNK), a Magnolia grandiflora derivative, bind to unfolded conformations of the GRP78 ATPase domain. Epigallocatechin gallate and HNK induced death in six neuroectodermal tumour cell lines tested. Levels of death to HNK were twice that for EGCG; half-maximal effective doses were similar but EGCG sensitivity varied more widely between cell types. Honokiol induced ER stress and UPR as predicted from its ability to interact with GRP78, but EGCG was less effective. With respect to cell death, HNK had synergistic effects on melanoma and glioblastoma cells with the ER stress inducers fenretinide or bortezomib, but only additive (fenretinide) or inhibitory (bortezomib) effects on neuroblastoma cells. Honokiol induces apoptosis due to ER stress from an interaction with GRP78. The data are consistent with DSC results that suggest that HNK binds to GRP78 more effectively than EGCG. Therefore, HNK may warrant development as an antitumour drug.
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DOI：
10.1074/jbc.m109.014092
发表时间：
2010-02-26
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Armstrong JL;Flockhart R;Veal GJ;Lovat PE;Redfern CP
通讯作者：
Redfern CP
影响因子：
2.9
作者：
Cheng, Niang;Xia, Tian;Ma, Jun Rong
通讯作者：
Ma, Jun Rong
影响因子：
3.6
作者：
Corazzari, M;Lovat, PE;Redfern, CPF
通讯作者：
Redfern, CPF
影响因子：
2.3
作者：
Haselsberger, K;Peterson, DC;Darling, JL
通讯作者：
Darling, JL
影响因子：
5.3
作者：
Blais, JD;Filipenko, V;Bell, JC
通讯作者：
Bell, JC