Chen Z P, Yan Y P, Ding Q J, Knapp S, Potenza J A, Schugar H J, Chen K Y
Department of Chemistry, State University of New Jersey, Piscataway 08855-0939, USA.
Cancer Lett. 1996 Aug 2;105(2):233-9. doi: 10.1016/0304-3835(96)04287-5.
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.
脱氧hypusine合酶以亚精胺为底物，催化真核起始因子5A（eIF-5A）前体上赖氨酸向脱氧hypusine残基的转化。随后，脱氧hypusine残基的羟基化完成了eIF-5A上hypusine的形成。多胺（腐胺、亚精胺和精胺）与肿瘤生长和分化有关。由于脱氧hypusine/hypusine的形成是最具特异性的多胺依赖性生化事件之一，我们决定使用N1-胍基-1,7-二氨基庚烷（GC7），一种脱氧hypusine合酶的有效抑制剂，来评估hypusine形成在肿瘤生长和分化中的作用。GC7在微摩尔浓度下抑制N2a小鼠神经母细胞瘤细胞和DS19小鼠红白血病细胞的生长。然而，在狭窄的浓度范围内，GC7在次优量的二丁酰cAMP存在下可促进小鼠神经母细胞瘤细胞的分化。相反，GC7阻断了由六亚甲基双乙酰胺诱导的DS19细胞的分化。先前已证明，用二氟甲基鸟氨酸（DFMO）消耗多胺可促进神经母细胞瘤细胞的分化，但抑制红细胞分化。由于我们的研究表明GC7模拟了DFMO对肿瘤分化的作用，DFMO对肿瘤分化的影响很可能是由hypusine形成介导的，并且GC7代表了一种更具特异性的抑制剂，可改变某些肿瘤细胞中的分化程序。
