CYTOSTASIS INDUCED IN L1210 MURINE LEUKEMIA-CELLS BY THE S-ADENOSYL-L-METHIONINE DECARBOXYLASE INHIBITOR 5'-([(Z)-4-AMINO-2-BUTENYL]METHYLAMINO)-5'-DEOXYADENOSINE MAY BE DUE TO HYPUSINE DEPLETION
CYTOSTASIS INDUCED IN L1210 MURINE LEUKEMIA-CELLS BY THE S-ADENOSYL-L-METHIONINE DECARBOXYLASE INHIBITOR 5'-([(Z)-4-AMINO-2-BUTENYL]METHYLAMINO)-5'-DEOXYADENOSINE MAY BE DUE TO HYPUSINE DEPLETION
复制标题
DOI：
10.1042/bj2870717
复制
发表时间：
1992-11-01
影响因子：
4.1
通讯作者：
PEGG, AE
中科院分区：
文献类型：
--
作者：
BYERS, TL;GANEM, B;PEGG, AE
使用小鼠白血病L1210细胞和5 ′-{[（Z）-4-氨基-2-丁烯基]甲氨基}-5 ′-脱氧腺苷（MDL 73811，AbeAdo）（S-腺苷酰-L-甲硫氨酸脱羧酶的酶激活的不可逆抑制剂）研究了形成亚精胺和精胺的能力的抑制对细胞生长的影响。腐胺水平增加了80倍，亚精胺和精胺水平大大降低后，3天的最大抑制剂量为10 μ M的AbeAdo曝光。向培养基中加入AbeAdo抑制了3天后测量的L1210细胞的生长，其抑制作用呈剂量依赖性，但是，即使在最有效的10 μ M剂量下，暴露于AbeAdo也不能立即抑制细胞生长。然而，长期暴露于10 μ M-AbeAdo的L1210细胞的生长速率稳定下降，直到第12天细胞停止生长。暴露于AbeAdo 12天的L1210细胞不能通过从培养物中去除药物而从细胞停滞中拯救出来，但可以通过暴露于外源性亚精胺或精胺而拯救出来，这表明AbeAdo的生长抑制作用是亚精胺和/或精胺耗尽的结果。这表明，在没有生理水平的亚精胺和精胺的情况下，阿贝替尼处理的细胞中升高的细胞内腐胺维持有限的生长，直到亚精胺（和/或精胺）实现的某些关键和特定的生理作用变得缺乏，导致细胞停滞。N-（3-氨基丙基）-1，4-二氨基-顺-丁-2-烯，亚精胺类似物，是脱氧羟腐胺赖氨酸合成酶的底物，能够模拟亚精胺逆转阿贝替尼诱导的细胞停滞的作用。亚精胺类似物，如5，5-二甲基亚精胺，不是脱氧羟腐胺赖氨酸合酶的底物，以这种方式没有活性。这些结果提供的证据表明，羟腐胺赖氨酸的蛋白质合成起始因子eIF-5A的形成可能是细胞生长所必需的亚精胺的关键作用。
The effects of inhibition of the capacity to form spermidine and spermine on cell growth were investigated using murine leukaemia L1210 cells and 5'-{[(Z)-4-amino-2-butenyl]methylamino}-5'-deoxyadenosine (MDL 73811, AbeAdo), an enzyme-activated irreversible inhibitor of S-adenoSyl-L-methionine decarboxylase. Putrescine levels were increased 80-fold, and spermidine and spermine levels were greatly reduced after a 3-day exposure to a maximally inhibitory dose of 10 muM-AbeAdo. Addition of AbeAdo to the culture medium inhibited the growth of L1210 cells measured 3 days later in a dose-dependent manner, but, even at a dose of 10 muM, which was maximally effective, exposure to AbeAdo was not immediately cytostatic. However, the growth rate of L1210 cells chronically exposed to 10 muM-AbeAdo declined steadily until day 12, when the cells stopped growing. L1210 cells exposed to AbeAdo for 12 days could not be rescued from cytostasis by removal of the drug from the culture, but could be rescued by exposure to exogenous spermidine or spermine, indicating that the growth-inhibitory effects of AbeAdo were a result of spermidine and/or spermine depletion. It is suggested that elevated intracellular putrescine in AbeAdo-treated cells sustained limited growth in the absence of physiological levels of spermidine and spermine until certain critical and specific physiological role(s) fulfilled by spermidine (and/or spermine) became deficient resulting in cytostasis. N-(3-Aminopropyl)-1,4-diamino-cis-but-2-ene, a spermidine analogue that is a substrate for deoxyhypusine synthase, was able to mimic the effects of spermidine in reversing AbeAdo-induced cytostasis. Spermidine analogues such as 5,5-dimethylspermidine, which are not substrates for deoxyhypusine synthase, were not active in this way. These results provide evidence that the formation of hypusine in the protein-synthesis initiation factor eIF-5A may be a critical role of spermidine essential for cell growth.