Growth inhibition of colon cancer cells by polyisoprenylated benzophenones is associated with induction of the endoplasmic reticulum response
Growth inhibition of colon cancer cells by polyisoprenylated benzophenones is associated with induction of the endoplasmic reticulum response
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DOI：
10.1002/ijc.23515
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发表时间：
2008-08-01
影响因子：
6.4
通讯作者：
Bernard, Weinstein I.
中科院分区：
文献类型：
--
作者：
Protiva, Petr;Hopkins, Michael E.;Bernard, Weinstein I.
从黄花藤黄中提取的聚异戊二烯基二苯甲酮具有体外细胞毒活性和在啮齿动物模型中的抗肿瘤活性，但其作用机制尚不清楚。本研究的目的是平行检测3种藤黄衍生的二苯甲酮类化合物--黄花青酚(X)、古替费酮E(GE)和古蒂费酮H(GH)在3种人结肠癌细胞系HCT116、HT29和SW480中的靶向分子通路。测定IC50浓度，然后用X、Ge或GH分别以各自的IC50或IC50x2浓度处理细胞。用流式细胞仪和半胱氨酸天冬氨酸氨基转移酶活性检测细胞周期、线粒体膜电位和细胞凋亡率。用Illumina 24K基因芯片检测基因表达的变化。我们发现X、Ge和GH在其IC50浓度下引起线粒体膜电位丧失和G1期停滞，在IC50X2浓度下诱导caspase激活。对基因表达变化的分析表明，在所有3种化合物和所有3种细胞系中，内质网应激反应的组成部分XBP1、ATF4和DDIT3/CHOP等几个基因的表达显著增加。MTOR生存通路的抑制因子DDIT4/Redd1基因也上调。因此，X、Ge和GH似乎至少部分地通过激活内质网应激反应和抑制mTOR细胞生存途径来抑制人结肠癌细胞的生长。这些综合作用可能有助于这些新化合物的抗癌活性。(C)2008年Wiley-Liss，Inc.
Polyisoprenylated benzophenones derived from Garcinia xanthochymus have cytotoxic activity in vitro and antitumor activity in rodent models, but the mechanism is unknown. The purpose of our study was to examine in parallel molecular pathways that are targeted by 3 Garcinia-derived benzophenones-xanthochymol (X), guttiferone E (GE) and guttiferone H (GH), in 3 human colon cancer cell lines, HCT116, HT29 and SW480. The IC50 concentrations were determined and the cells were then treated with X, GE or GH at their respective IC50 or IC50x2 concentrations. Effects on the cell cycle, mitochondrial membrane potential and apoptosis were assessed by flow cytometry and caspase activation. Changes in gene expression were assessed with Illumina 24 K gene arrays. We found that X, GE and GH induced loss of mitochondrial membrane potential and G1 arrest at their IC50 concentrations and induced caspase activation at IC50 X 2 concentrations. An analysis of the changes in gene expression revealed that with all 3 compounds and all 3 cell lines there was a marked increase in expression of several genes, including XBP1, ATF4 and DDIT3/CHOP, which are components of the endoplasmic reticulum stress response. The DDIT4/REDD1 gene, an inhibitor of the mTOR survival pathway, was also up-regulated. Therefore, X, GE and GH appear to inhibit the growth of human colon cancer cells, at least in part, by activating the endoplasmic reticulmn stress response and inhibiting the mTOR cell survival pathway. These combined effects may contribute to the anticancer activity of these novel compounds. (c) 2008 Wiley-Liss, Inc.