Journal Article

APC-dependent changes in expression of genes influencing polyamine metabolism, and consequences for gastrointestinal carcinogenesis, in the <i>Min</i> mouse

Steven H. Erdman, Natalia A. Ignatenko, Marianne B. Powell, Karen A. Blohm-Mangone, Hana Holubec, José M. Guillén-Rodriguez and Eugene W. Gerner

in Carcinogenesis

Volume 20, issue 9, pages 1709-1713
Published in print September 1999 | ISSN: 0143-3334
Published online September 1999 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/20.9.1709
APC-dependent changes in expression of genes influencing polyamine metabolism, and consequences for gastrointestinal carcinogenesis, in the Min mouse

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The colorectal mucosa of pre-symptomatic individuals with familial adenomatous polyposis (FAP) contains elevated levels of the proliferation-associated polyamines. The Min mouse, like humans with FAP, expresses an abnormal genotype for the APC tumor suppressor gene. In order to determine how APC mutation influences intestinal tissue polyamine content, we measured steady-state RNA levels of ornithine decarboxylase (ODC), the first enzyme in polyamine synthesis, antizyme (AZ), a protein which negatively regulates ODC, and the spermidine/spermine N1-acetyltransferase (SSAT), the first enzyme in polyamine catabolism. RNA content was increased 6- to 8-fold in both the small intestine and colon for ODC, decreased significantly in the small intestine but not the colon for AZ and was not statistically different in either intestinal tissue for SSAT in Min mice compared with normal littermates. Consistent with the changes in ODC and AZ gene expression, small intestinal, but not colonic, polyamine content was elevated in Min mice compared with normal littermates. Treatment of Min mice with the specific ODC inhibitor difluoromethylornithine (DFMO) suppressed small intestinal, but not colonic, polyamine content and tumor number. These data indicate that small intestinal tissue polyamine content is elevated in Min mice by a mechanism involving APC-dependent changes in ODC and AZ RNA. Further, ODC enzyme activity, which is influenced by both ODC and AZ RNA levels and inhibited by DFMO, is consequential for small intestinal tumorigenesis in this model. In the FAP population, DFMO may be of value in the chemoprevention of small intestinal adenocarcinoma that remains a risk following colectomy.

Keywords: APC, adenomatous polyposis coli; AZ, antizyme; COX-2, cyclooxygenase-2; DFMO, difluoromethylornithine; FAP, familial adenomatous polyposis; GAPD, glyceraldehyde 3-phosphate dehydrogenase; ODC, ornithine decarboxylase; SSAT, spermidine/spermine N1-acetyltransferase.

Journal Article.  3495 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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