Deoxyhpusine synthase catalyzes the conversion of
lysine to
deoxyhypusine residue on the eukaryotic
initiation factor 5A (eIF-5A) precursor using
spermidine as the substrate. Subsequent hydroxylation of the
deoxyhypusine residue completes
hypusine formation on
eIF-5A.
Polyamines (
putrescine,
spermidine, and
spermine) have been implicated in
tumor growth and differentiation. Because
deoxyhypusine/
hypusine formation is one of the most specific
polyamine-dependent biochemical events, we decided to use N1-guanyl-1,7-diaminoheptane (GC7), a potent inhibitor for
deoxyhypusine synthase, to assess the role of
hypusine formation on
tumor growth and differentiation. GC7 suppressed the growth of N2a mouse
neuroblastoma cells and DS19 murine
erythroleukemia cells at micromolar concentrations. However, within a narrow concentration range, GC7 could promote the differentiation of mouse
neuroblastoma cells in the presence of suboptimal amount of dibutyryl cAMP. In contrast, GC7 blocked the differentiation of DS19 cells induced with
hexamethylene bisacetamide.
Polyamine depletion by difluoromethyl
ornithine (DFMO) has previously been shown to promote differentiation of
neuroblastoma cells but inhibits erythrodifferentiation. Since our studies demonstrated that GC7 mimics the action of DFMO on
tumor differentiation, it is likely that the effect of DFMO on
tumor differentiation is mediated by
hypusine formation and that GC7 represents a more specific inhibitor that can alter the differentiation program in certain
tumor cells.