3,3'-diindolylmethane enhances the efficacy of butyrate in colon cancer prevention through down-regulation of survivin.
3,3'-diindolylmethane enhances the efficacy of butyrate in colon cancer prevention through down-regulation of survivin.
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DOI：
10.1158/1940-6207.capr-08-0142
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发表时间：
2009-06
期刊：
影响因子：
--
通讯作者：
Guo B
中科院分区：
文献类型：
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作者：
Bhatnagar N;Li X;Chen Y;Zhou X;Garrett SH;Guo B
丁酸盐是组蛋白去乙酰化酶（HDAC）的抑制剂，已被广泛评价为结肠癌的化学预防剂。我们最近证明，结肠腺瘤性息肉病（APC）基因中的突变赋予结肠癌对HDAC介导的细胞凋亡的抗性（Huang和Guo，Cancer Research，66（18），9245-9251，2006）。在这里，我们发现APC突变使结肠癌细胞对丁酸盐诱导的凋亡具有抵抗力，这是由于丁酸盐未能下调这些细胞中的生存素。另一种癌症预防剂3，3 ′-二吲哚甲烷（DIM）被鉴定为能够下调表达突变APC的结肠癌中的存活素。DIM通过抑制p34 cdc 2-cyclin B1介导的survivin Thr 34磷酸化，抑制survivin mRNA表达，促进survivin蛋白降解。DIM预处理增强丁酸诱导表达突变APC的结肠癌细胞凋亡。DIM/丁酸盐组合处理诱导促凋亡Bax和巴克蛋白的表达，触发Bax二聚化/活化，并引起细胞色素c和Smac蛋白从线粒体释放。虽然生存素的过表达阻断了DIM/丁酸盐诱导的凋亡，但通过siRNA敲低生存素增加了结肠癌细胞中丁酸盐诱导的凋亡。我们进一步证明，DIM能够下调生存素，增强丁酸盐在APC min/+小鼠中诱导凋亡和预防家族性腺瘤性息肉病的作用。因此，DIM和丁酸盐的组合可能是预防结肠癌的有效策略。
Butyrate is an inhibitor of histone deacetylase (HDAC) and has been extensively evaluated as a chemoprevention agent for colon cancer. We recently demonstrated that mutations in the adenomatous polyposis coli (APC) gene confer resistance to HDAC inhibitor-induced apoptosis in colon cancers (Huang and Guo, Cancer Research, 66(18), 9245-9251, 2006). Here we show that APC mutation rendered colon cancer cells resistant to butyrate-induced apoptosis due to the failure of butyrate to down-regulate survivin in these cells. Another cancer preventive agent, 3,3′-Diindolylmethane (DIM), was identified to be able to down-regulate survivin in colon cancers expressing mutant APC. DIM inhibited survivin mRNA expression and promoted survivin protein degradation through inhibition of p34cdc2-cyclin B1-mediated survivin Thr34 phosphorylation. Pre-treatment with DIM enhanced butyrate-induced apoptosis in colon cancer cells expressing mutant APC. DIM/butyrate combination treatment induced the expression of pro-apoptotic Bax and Bak proteins, triggered Bax dimerization/activation, and caused release of cytochrome c and Smac proteins from mitochondria. While overexpression of survivin blocked DIM/butyrate-induced apoptosis, knocking-down of survivin by siRNA increased butyrate-induced apoptosis in colon cancer cells. We further demonstrated that DIM was able to down-regulate survivin and enhance the effects of butyrate in apoptosis induction and prevention of familial adenomatous polyposis in APCmin/+ mice. Thus, the combination of DIM and butyrate is potentially an effective strategy for the prevention of colon cancer.