In vivo regulation of colonic cell proliferation, differentiation, apoptosis, and P27Kip1 by dietary fish oil and butyrate in rats.
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.
Department of Nutrition and Food Science, Texas A&M University, College Station, Texas. School of Food and Nutritional Sciences, San Diego State University, San Diego, California. mhong2@mail.sdsu.edu.
Mee Young
MY
Hong
Department of Nutrition and Food Science, Texas A&M University, College Station, Texas.
Nancy D
ND
Turner
Deptartment of Statistics, Texas A&M University, College Station, Texas.
Mary E
ME
Murphy
Department of Nutrition and Food Science, Texas A&M University, College Station, Texas. Deptartment of Statistics, Texas A&M University, College Station, Texas.
Raymond J
RJ
Carroll
Department of Nutrition and Food Science, Texas A&M University, College Station, Texas.
Robert S
RS
Chapkin
Department of Nutrition and Food Science, Texas A&M University, College Station, Texas.
Joanne R
JR
Lupton
D000818:Animals; D017209:Apoptosis; D001397:Azoxymethane / Q000737:chemistry; D002087:Butyrates / Q000008:administration & dosage*; D002454:Cell Differentiation; D049109:Cell Proliferation; D003106:Colon / Q000473:pathology*; D003110:Colonic Neoplasms / Q000473:pathology / Q000517:prevention & control*; D003314:Corn Oil / Q000008:administration & dosage; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D004249:DNA Damage; D004042:Dietary Fats, Unsaturated / Q000008:administration & dosage; D005285:Fermentation; D005395:Fish Oils / Q000008:administration & dosage*; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D010368:Pectins / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley
D002087:Butyrates; C493962:Cdkn1b protein, rat; D004042:Dietary Fats, Unsaturated; D005395:Fish Oils; D019394:Ki-67 Antigen; D050760:Cyclin-Dependent Kinase Inhibitor p27; D003314:Corn Oil; D010368:Pectins; D001397:Azoxymethane