Butyrate has potent anti-tumorigenic effects on many
colon cancer cell lines, including inhibition of growth and promotion of apoptosis in vitro. Nevertheless, despite the
butyrate concentration in the colonic lumen being sufficient to result in the death of almost all cells in vitro,
colon cancers still develop and grow in vivo, suggesting that
cancer cells must develop mechanisms by which they escape the effects of
butyrate observed in vitro.
Insulin-like growth factor-II (
IGF-II) is an autocrine
growth factor in many
colon cancer cells. The aim of this study was to determine whether
IGF-II influences
butyrate-mediated apoptosis in LIM 2405 human
colon cancer cells.
Butyrate and
trichostatin A, both of which are
histone deacetylase inhibitors although the latter is more specific, induced apoptosis as determined by floating cell counting,
Hoechst 33258 staining,
DNA laddering and a cell death detection ELISA.
IGF-II inhibited the effects of both agents.
Butyrate but not
trichostatin A also induced LIM 2405 cell migration. In contrast to the above results,
IGF-II enhanced
butyrate-induced cell migration. Levels of IGF binding protein-3 (IGFBP-3), which may induce apoptosis by IGF-dependent or -independent mechanisms, were increased by
butyrate and
trichostatin A;
IGF-II augmented this effect. It is therefore unlikely that
IGFBP-3 mediates
butyrate-induced apoptosis. We suggest that
IGF-II inhibits the pro-apoptotic effect of
butyrate downstream of
histone deacetylase inhibition. In contrast,
IGF-II promotes
histone deacetylase-dependent
IGFBP-3 expression and
histone deacetylase-independent migration.
IGF-II may promote tumour growth by mediating the development of resistance to the pro-apoptotic effects of
butyrate.