Kubota M, Kajander E O, Carson D A
Cancer Res. 1985 Aug;45(8):3567-72.
The control of polyamine synthesis in neoplastic cells is complex and incompletely understood. Using murine lymphoma cells deficient in methylthioadenosine (MTA) phosphorylase, we have analyzed the role of MTA in the regulation of ornithine decarboxylase and S-adenosylmethionine (SAM) decarboxylase, the two rate-limiting enzymes in the polyamine-biosynthetic pathway. The addition of MTA to the enzyme-deficient lymphoblasts induced within 1 to 3 h an increase in the activities of both decarboxylases and an accompanying rise in putrescine and decarboxylated SAM levels. The ornithine decarboxylase inhibitor alpha-difluoromethylornithine blocked the MTA-triggered accumulation of putrescine but not decarboxylated SAM. In a reciprocal manner, the SAM decarboxylase inhibitor methylglyoxal bis(guanylhydrazone) prevented the accretion of decarboxylated SAM but not putrescine. The MTA-induced rise in SAM decarboxylase and ornithine decarboxylase activities preceded by several hours changes in spermidine or spermine pools. However, MTA decreased the flux through the polyamine-synthetic pathway, as estimated by the incorporation of radioactive ornithine into spermine. Similar changes in polyamine metabolism were observed in a secondary mutant deficient in MTA phosphorylase, but resistant to MTA toxicity. These results suggest that the velocity of polyamine synthesis, or the concentration of MTA itself, may regulate ornithine decarboxylase and SAM decarboxylase activities through separate, growth-independent mechanisms.
肿瘤细胞中多胺合成的调控复杂且尚未完全明确。我们利用缺乏甲硫腺苷（MTA）磷酸化酶的小鼠淋巴瘤细胞，分析了MTA在鸟氨酸脱羧酶和S-腺苷甲硫氨酸（SAM）脱羧酶调控中的作用，这两种酶是多胺生物合成途径中的限速酶。向缺乏该酶的淋巴母细胞中添加MTA，在1至3小时内诱导两种脱羧酶的活性增加，同时腐胺和脱羧化SAM水平也随之升高。鸟氨酸脱羧酶抑制剂α-二氟甲基鸟氨酸可阻断MTA引发的腐胺积累，但不能阻断脱羧化SAM的积累。反之，SAM脱羧酶抑制剂甲基乙二醛双（脒基腙）可阻止脱羧化SAM的增加，但不能阻止腐胺的增加。MTA诱导的SAM脱羧酶和鸟氨酸脱羧酶活性升高比亚精胺或精胺池的变化提前数小时。然而，通过放射性鸟氨酸掺入精胺的量估算，MTA降低了多胺合成途径的通量。在另一种缺乏MTA磷酸化酶但对MTA毒性有抗性的二级突变体中，也观察到了类似的多胺代谢变化。这些结果表明，多胺合成的速度或MTA本身的浓度可能通过独立于生长的机制分别调节鸟氨酸脱羧酶和SAM脱羧酶的活性。
