We have shown that dietary
fish oil is protective against experimentally induced
colon cancer, and the protective effect is enhanced by coadministration of
pectin. However, the underlying mechanisms have not been fully elucidated. We hypothesized that
fish oil with
butyrate, a
pectin fermentation product, protects against
colon cancer initiation by decreasing cell proliferation and increasing differentiation and apoptosis through a p27(Kip1)-mediated mechanism. Rats were provided diets of corn or
fish oil, with/without
butyrate, and terminated 12, 24, or 48 hours after
azoxymethane (AOM) injection. Proliferation (Ki-67), differentiation (
Dolichos Biflorus Agglutinin), apoptosis (TUNEL), and p27(Kip1) (cell-cycle mediator) were measured in the same cell within crypts in order to examine the coordination of cell cycle as a function of diet. DNA damage (N(7)-methylguanine) was determined by quantitative IHC analysis. Dietary
fish oil decreased DNA damage by 19% (P = 0.001) and proliferation by 50% (P = 0.003) and increased differentiation by 56% (P = 0.039) compared with
corn oil. When combined with
butyrate,
fish oil enhanced apoptosis 24 hours after AOM injection compared with a
corn oil/
butyrate diet (P = 0.039). There was an inverse relationship between crypt height and apoptosis in the
fish oil/
butyrate group (r = -0.53, P = 0.040). The
corn oil/
butyrate group showed a positive correlation between p27(Kip1) expression and proliferation (r = 0.61, P = 0.035). These results indicate the in vivo effect of
butyrate on apoptosis and proliferation is dependent on dietary
lipid source. These results demonstrate the presence of an early coordinated colonocyte response by which
fish oil and
butyrate protects against colon
tumorigenesis.