Welcome
to the Berger Lab!
Potent modulation of intestinal
tumorigenesis in
Apcmin/+ mice by the polyamine catabolic enzyme spermidine/spermine
N1-acetyltransferase.
Tucker JM, Murphy JT, Kisiel N, Diegelman P, Barbour KW, Davis C,
Medda M, Alhonen L, Janne J, Kramer DL, Porter CW, Berger FG.
Department of Biological Sciences, University of South Carolina,
Columbia, South Carolina, USA.
Intracellular
polyamine pools are homeostatically maintained by processes involving
biosynthesis, catabolism, and transport. Although most polyamine-based
anticancer strategies target biosynthesis, we recently showed that
activation of polyamine catabolism at the level of spermidine/spermine
N(1)-acetyltransferase-1 (SSAT) suppresses tumor outgrowth in a mouse
prostate cancer model. Herein, we examined the effects of differential
SSAT expression on intestinal tumorigenesis in the Apc(Min/+) (MIN)
mouse. When MIN mice were crossed with SSAT-overproducing transgenic
mice, they developed 3- and 6-fold more adenomas in the small intestine
and colon, respectively, than normal MIN mice. Despite accumulation of
the SSAT product, N(1)-acetylspermidine, spermidine and spermine pools
were only slightly decreased due to a huge compensatory increase in
polyamine biosynthetic enzyme activities that gave rise to enhanced
metabolic flux. When MIN mice were crossed with SSAT knock-out mice,
they developed 75% fewer adenomas in the small intestine, suggesting
that under basal conditions, SSAT contributes significantly to the MIN
phenotype. Despite the loss in catabolic capability, tumor spermidine
and spermine pools failed to increase significantly due to a
compensatory decrease in biosynthetic enzyme activity giving rise to a
reduced metabolic flux. Loss of heterozygosity at the Apc locus was
observed in tumors from both SSAT-transgenic and -deficient MIN mice,
indicating that loss of heterozygosity remained the predominant
oncogenic mechanism. Based on these data, we propose a model in which
SSAT expression alters flux through the polyamine pathway giving rise
to metabolic events that promote tumorigenesis. The finding that
deletion of SSAT reduces tumorigenesis suggests that small-molecule
inhibition of the enzyme may represent a nontoxic prevention and/or
treatment strategy for gastrointestinal cancers.
PMID: 15958588 [PubMed - in process]
PubMed
link
Back
to Biology Home Page
Back
to Frank Berger Home Page
Back
to Berger Lab Home Page