EFFECTS OF INHIBITORS OF DEOXYHYPUSINE SYNTHASE ON THE DIFFERENTIATION OF MOUSE NEUROBLASTOMA AND ERYTHROLEUKEMIA-CELLS

Deoxyhypusine synthase catalyzes the conversion of lysine to deoxyhypu sine residue on the eukaryotic initiation factor 5A (eIF-5A) precursor using spermidine as the substrate. Subsequent hydroxylation of the de oxyhypusine residue completes hypusine formation on eIF-5A. Polyamines (putrescine, spermidine, and spermine) have been implicated in tumor growth and differentiation. Because deoxyhypusine/hypusine formation i s one of the most specific polyamine-dependent biochemical events, we decided to use N-1-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 mic romolar 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 b isacetamide. Polyamine depletion by difluoromethyl ornithine (DFMO) ha s previously been shown to promote differentiation of neuroblastoma ce lls but inhibits erythrodifferentiation. Since our studies demonstrate d that GC7 mimics the action of DFMO on tumor differentiation, it is l ikely that the effect of DFMO on tumor differentiation is mediated by hypusine formation and that GC7 represents a more specific inhibitor t hat can alter the differentiation program in certain tumor cells.