Ornithine decarboxylase (ODC) is subject to feedback regulation by the
polyamines. Thus, addition of
putrescine,
spermidine or
spermine to cells causes inhibition of ODC mRNA translation.
Putrescine and
spermine are readily converted into
spermidine. Therefore, it is conceivable that the inhibition of ODC synthesis observed in
putrescine- and
spermine-supplemented cells is instead an effect of
spermidine. To examine this possibility we have used two analogs of
putrescine and
spermine, namely
1,4-dimethylputrescine and
5,8-dimethylspermine, which cannot be converted into
spermidine. Both analogs were found to inhibit the incorporation of [35S]
methionine into ODC
protein to approximately the same extent, suggesting that
putrescine as well as
spermine exert a negative feedback control of ODC mRNA translation in the cell. In addition to suppressing ODC synthesis, both analogs were found to increase the turnover rate of the
enzyme.
5,8-Dimethylspermine caused a marked decrease in the activity of
S-adenosylmethionine decarboxylase (AdoMetDC). This effect was not obtained with
1,4-dimethylputrescine, indicating that
spermine, but not
putrescine, exerts a negative control of AdoMetDC. Treatment with
1,4-dimethylputrescine caused extensive depletion of the cellular
putrescine and
spermidine content, but accumulation of
spermine.
5,8-Dimethylspermine treatment, on the other hand, effectively depleted the
spermine content and had less effect on the
putrescine and
spermidine content, at least initially. Nevertheless, the total
polyamine content was more extensively reduced by treatment with
5,8-dimethylspermine than with
1,4-dimethylputrescine. Accordingly, only
5,8-dimethylspermine treatment exerted a significant inhibitory effect on
Ehrlich ascites tumor cell growth.