Numerous studies have demonstrated a link between elevated
polyamine biosynthesis and neoplastic growth, but the specific contribution of
spermine synthase to epithelial
tumor development has never been explored in vivo. Mice with widespread overexpression of
spermine synthase (CAG-SpmS) exhibit decreased
spermidine levels, increased
spermine and a significant rise in tissue
spermine:
spermidine ratio. We characterized the response of CAG-SpmS mice to two-stage skin chemical
carcinogenesis as well as spontaneous intestinal
carcinogenesis induced by loss of the Apc
tumor suppressor in Apc (Min) (/+) (Min) mice. CAG-SpmS mice maintained the canonical increases in
ornithine decarboxylase (ODC) activity,
polyamine content and epidermal thickness in response to
tumor promoter treatment of the skin. The induction of
S-adenosylmethionine decarboxylase (AdoMetDC) activity and its product decarboxylated
AdoMet were impaired in CAG-SpmS mice, and the
spermine:
spermidine ratio was increased 3-fold in both untreated and 12-O-tetradecanoylphorbol-13-acetate (TPA)-treated skin. The susceptibility to 7,12-dimethylbenz[a]
anthracene (DMBA)/TPA skin
carcinogenesis was not altered in CAG-SpmS mice, and SpmS overexpression did not modify the previously described
tumor resistance of mice with targeted antizyme expression or the enhanced
tumor response in mice with targeted
spermidine/
spermine-N ( 1) -
acetyltransferase expression. CAG-SpmS/Min mice also exhibited elevated
spermine:
spermidine ratios in the small intestine and colon, yet their
tumor multiplicity and size was similar to Min mice. Therefore, studies in two of the most widely used
tumorigenesis models demonstrate that increased
spermine synthase activity and the resulting elevation of the
spermine:
spermidine ratio does not alter susceptibility to
tumor development initiated by c-Ha-Ras mutation or Apc loss.