Bcl-2 family-mediated apoptotic effects of 3,3′-diindolylmethane (DIM) in human breast cancer cells
Bcl-2 family-mediated apoptotic effects of 3,3′-diindolylmethane (DIM) in human breast cancer cells
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DOI：
10.1016/s0006-2952(02)00856-0
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发表时间：
2002-03-15
影响因子：
5.8
通讯作者：
Bjeldanes, LF
中科院分区：
文献类型：
--
作者：
Hong, C;Firestone, GL;Bjeldanes, LF
3，3 '-二吲哚基甲烷（DIM）是存在于芸苔属蔬菜中的推定抗癌剂吲哚-3-甲醇（I3 C）的主要体内衍生物。在浓度高于10 μ M时，DIM以浓度和时间依赖性方式抑制雌激素受体完全（MCF-7）和缺陷（MDA-MB-231）的人乳腺癌细胞中的DNA合成和细胞增殖。这些抗增殖作用伴随着两种细胞系中程序性细胞死亡的特征性指征，包括磷脂酰丝氨酸的外化、染色质凝聚和DNA片段化。此外，Western和北方印迹分析，以及免疫共沉淀分析，揭示了在MCF-7和MDA-MB-231细胞，DIM处理降低总转录和蛋白水平的凋亡抑制蛋白Bcl-2。以及与促凋亡蛋白Bax结合的Bcl-2的量。DIM处理还引起Bax蛋白水平的增加，但不影响与Bcl-2结合的Bax的水平，作为Bcl-2下调在DIM诱导的凋亡反应中的作用的功能测试。Bcl-2在MCF-7细胞中的异位表达减弱了DIM的凋亡作用。这些结果表明，DIM可以诱导乳腺癌细胞凋亡，而不依赖于雌激素受体状态，这一过程是由Bax/Bcl-2家族凋亡调节因子的调节表达介导的。(C)2002年爱思唯尔科学公司All rights reserved.
3,3'-Diindolylmethane (DIM) is a major in vivo derivative of the putative anticancer agent indole-3-carbinol (I3C), which is present in vegetables of the Brassica genus. At concentrations above 10 muM, DIM inhibited DNA synthesis and cell proliferation in both estrogen receptor replete (MCF-7) and deficient (MDA-MB-231) human breast cancer cells in a concentration- and time-dependent manner. These antiproliferative effects were accompanied by characteristic indications of programmed cell death in both cell lines, including externalization of phosphatidylserine, chromatin condensation, and DNA fragmentation. Furthermore, Western and Northern blot analyses, as well as coimmunoprecipitation assays, revealed that in both MCF-7 and MDA-MB-231 cells, DIM treatment decreased total transcript and protein levels of the apoptosis inhibitory protein Bcl-2. and the amount of Bcl-2 bound to the pro-apoptotic protein Bax. DIM treatment also caused an increase in Bax protein levels, but did not affect the level of Bax that was bound to Bcl-2, As a functional test of the role of Bcl-2 down-regulation in the DIM-induced apoptotic response. ectopic expression of Bcl-2 in MCF-7 cells was shown to attenuate the apoptotic effect of DIM. These results demonstrate that DIM can induce apoptosis in breast cancer cells independent of estrogen receptor status by a process that is mediated by the modulated expression of the Bax/Bcl-2 family of apoptotic regulatory factors. (C) 2002 Elsevier Science Inc. All rights reserved.