Induction of caspase-3 protease activity and apoptosis by butyrate and trichostatin a (Inhibitors of histone deacetylase): Dependence on protein synthesis and synergy with a mitochondrial/cytochrome c-dependent pathway

Vicente Medina, Belinda Edmonds, Graeme P. Young, Roberta James, Sarah Appleton, Peter David Zalewski

Research output: Contribution to journalArticle

358 Citations (Scopus)

Abstract

The induction of apoptosis of tumor cells by the colonic fermentation product butyrate is thought to be an important mechanism in protection against colorectal cancer. Because a major action of butyrate is to inhibit histone deacetylase (leading to chromatin relaxation and altered gene expression), butyrate may induce apoptosis by derepression of specific cell death genes. Here we show that butyrate and trichostatin A (a more selective inhibitor of histone deacetylase) induce the same program of apoptosis in Jurkat lymphoid and LIM 1215 colorectal cancer cell lines that is strictly dependent on new protein synthesis (within 10 h) and that leads to the conversion of the proenzyme form of caspase-3 to the catalytically active effector protease (within 16 h) and apoptotic death (within 24 h). Cells primed with a low concentration of butyrate that itself did not induce activation of caspase-3 or apoptosis were, nevertheless, rendered highly susceptible to induction of apoptosis by staurosporine (an agent that has recently been shown to act by causing mitochondrial release of cytochrome c). Synergy between butyrate and staurosporine was due to the presence of a factor in the cytosol of butyrate-primed cells which enhanced over 7-fold the activation of caspase-3 induced by the addition of cytochrome c and dATP to isolated cytosol. We propose that changes at the level of chromatin structure, induced by a physiological substance butyrate, lead to the expression of a protein that facilitates the pathway by which mitochondria activate caspase-3 and trigger apoptotic death of lymphoid and colorectal cancer cells.
Original languageEnglish
Pages (from-to)3697-3707
Number of pages11
JournalCancer Research
Volume57
Issue number17
Publication statusPublished - Sep 1997
Externally publishedYes

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