TY - JOUR
T1 - Role of polyamines in arginine-dependent colon carcinogenesis in Apc Min/+ mice
AU - Yerushalmi, Hagit F.
AU - Besselsen, David G.
AU - Ignatenko, Natalia A.
AU - Blohm-Mangone, Karen A.
AU - Padilla-Torres, Jose L.
AU - Stringer, David E.
AU - Guillen, Jose M.
AU - Holubec, Hana
AU - Payne, Claire M.
AU - Gerner, Eugene W.
PY - 2006/10
Y1 - 2006/10
N2 - We evaluated the role of polyamines in arginine-dependent intestinal tumorigenesis in ApcMin/+ mice. Arginine is a substrate for ornithine synthesis and thus can influence polyamine production. Supplementing the diet with arginine increased intestinal and colonic polyamine levels and colonic carcinogenesis. Inhibiting polyamine synthesis with D,L-α- diflouromethylornithine (DFMO) decreased small intestinal and colonic polyamine pools. In mice provided basal diet, but not when supplemented with arginine, DFMO decreased small intestinal tumor number and burden, and increased intestinal apoptosis. In mice provided supplemental arginine in the diet, DFMO induced late apoptosis and decreased tumorigenesis in the colon. DFMO slightly reduced tumor incidence, number, and size while significantly decreasing tumor burden and grade. These changes in colon tumorigenesis did not occur in mice not provided supplemental arginine. Our study indicates that polyamines play unique roles in intestinal and colonic carcinogenesis in ApcMin/+ mice. Inhibition of polyamine synthesis suppresses the arginine-dependent risk of colon tumorigenesis, resulting in apoptosis induction and decreased tumorigenesis, in this murine model.
AB - We evaluated the role of polyamines in arginine-dependent intestinal tumorigenesis in ApcMin/+ mice. Arginine is a substrate for ornithine synthesis and thus can influence polyamine production. Supplementing the diet with arginine increased intestinal and colonic polyamine levels and colonic carcinogenesis. Inhibiting polyamine synthesis with D,L-α- diflouromethylornithine (DFMO) decreased small intestinal and colonic polyamine pools. In mice provided basal diet, but not when supplemented with arginine, DFMO decreased small intestinal tumor number and burden, and increased intestinal apoptosis. In mice provided supplemental arginine in the diet, DFMO induced late apoptosis and decreased tumorigenesis in the colon. DFMO slightly reduced tumor incidence, number, and size while significantly decreasing tumor burden and grade. These changes in colon tumorigenesis did not occur in mice not provided supplemental arginine. Our study indicates that polyamines play unique roles in intestinal and colonic carcinogenesis in ApcMin/+ mice. Inhibition of polyamine synthesis suppresses the arginine-dependent risk of colon tumorigenesis, resulting in apoptosis induction and decreased tumorigenesis, in this murine model.
KW - Arginine
KW - D,L-α-diflouromethylornithine (DFMO)
KW - Intestinal and colonic carcinogenesis
KW - Min mice
KW - Polyamines
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U2 - 10.1002/mc.20246
DO - 10.1002/mc.20246
M3 - Article
C2 - 16705737
AN - SCOPUS:33749251088
VL - 45
SP - 764
EP - 773
JO - Molecular Carcinogenesis
JF - Molecular Carcinogenesis
SN - 0899-1987
IS - 10
ER -