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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Adenocarcinoma / genetics
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Adenocarcinoma / metabolism
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Adenocarcinoma / pathology
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Adenocarcinoma / prevention & control*
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Adenomatous Polyposis Coli / drug therapy
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Adenomatous Polyposis Coli / pathology
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Animals
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Anticarcinogenic Agents / administration & dosage
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Anticarcinogenic Agents / pharmacology*
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Anticarcinogenic Agents / therapeutic use
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Apoptosis / drug effects
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Butyrates / administration & dosage
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Butyrates / pharmacology*
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Butyrates / therapeutic use
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Cell Line, Tumor / drug effects
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Cell Line, Tumor / metabolism
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Colonic Neoplasms / genetics
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Colonic Neoplasms / metabolism
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Colonic Neoplasms / pathology
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Colonic Neoplasms / prevention & control*
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DNA, Complementary / genetics
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Down-Regulation / drug effects
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Drug Synergism
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Gene Expression Regulation, Neoplastic / drug effects
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Genes, APC
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Histone Deacetylase Inhibitors
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Humans
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Indoles / administration & dosage
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Indoles / pharmacology*
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Indoles / therapeutic use
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Inhibitor of Apoptosis Proteins
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Mice
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Mice, Mutant Strains
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Microtubule-Associated Proteins / antagonists & inhibitors*
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Microtubule-Associated Proteins / biosynthesis
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Microtubule-Associated Proteins / genetics
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Neoplasm Proteins / antagonists & inhibitors*
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Neoplasm Proteins / biosynthesis
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Neoplasm Proteins / genetics
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Recombinant Fusion Proteins / antagonists & inhibitors
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Survivin
Substances
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Anticarcinogenic Agents
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BIRC5 protein, human
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Butyrates
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DNA, Complementary
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Histone Deacetylase Inhibitors
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Indoles
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Inhibitor of Apoptosis Proteins
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Microtubule-Associated Proteins
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Neoplasm Proteins
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Recombinant Fusion Proteins
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Survivin
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3,3'-diindolylmethane