3,3 '-Diindolylmethane Enhances the Efficacy of Butyrate in Colon Cancer Prevention through Down-Regulation of Survivin
Bhatnagar, N; Li, Xia; Chen, Yue; Zhou, X; Garrett, SH; Guo, Bin
HERO ID
1456659
Reference Type
Journal Article
Year
2009
Language
English
PMID
| HERO ID | 1456659 |
|---|---|
| In Press | No |
| Year | 2009 |
| Title | 3,3 '-Diindolylmethane Enhances the Efficacy of Butyrate in Colon Cancer Prevention through Down-Regulation of Survivin |
| Authors | Bhatnagar, N; Li, Xia; Chen, Yue; Zhou, X; Garrett, SH; Guo, Bin |
| Journal | Cancer Prevention Research |
| Volume | 2 |
| Issue | 6 |
| Page Numbers | 581-589 |
| Abstract | Butyrate is an inhibitor of histone deacetylase (HDAC) and has been extensively evaluated as a chemoprevention agent for colon cancer. We recently showed that mutations in the adenomatous polyposis coli (APC) gene confer resistance to HDAC inhibitor-induced apoptosis in colon cancers. 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 p34(cdc2)-cyclin B1-mediated survivin Thr(34) phosphorylation. Pretreatment with DIM enhanced butyrate-induced apoptosis in colon cancer cells expressing mutant APC. DIM/butyrate combination treatment induced the expression of proapoptotic Bax and Bak proteins, triggered Bax dimerization/activation, and caused release of cytochrome c and Smac proteins from mitochondria. Whereas overexpression of survivin blocked DIM/butyrate-induced apoptosis, knocking down of survivin by small interfering RNA increased butyrate-induced apoptosis in colon cancer cells. We further showed that DIM was able to down-regulate survivin and enhance the effects of butyrate in apoptosis induction and prevention of familial adenomatous polyposis in APC(min/+) mice. Thus, the combination of DIM and butyrate is potentially an effective strategy for the prevention of colon cancer. |
| Doi | 10.1158/1940-6207.CAPR-08-0142 |
| Pmid | 19470789 |
| Wosid | WOS:000266629700011 |
| Is Certified Translation | No |
| Dupe Override | No |
| Comments | Source: Web of Science WOS:000266629700011 |
| Is Public | Yes |
| Language Text | English |