Multiple adaptive mechanisms affect asparagine synthetase substrate availability in asparaginase-resistant MOLT-4 human leukaemia cells
Multiple adaptive mechanisms affect asparagine synthetase substrate availability in asparaginase-resistant MOLT-4 human leukaemia cells
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DOI：
10.1042/0264-6021:3580059
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发表时间：
2001-08-15
影响因子：
4.1
通讯作者：
Kilberg, MS
中科院分区：
文献类型：
--
作者：
Aslanian, AM;Kilberg, MS
儿童急性淋巴细胞白血病的治疗是联合化疗与一些药物，几乎总是包括酶L-天冬酰胺酶（ASNase）。虽然初始缓解率相当高，但复发和相关的耐药性仍然是一个问题。体外研究表明，天冬酰胺合成酶（AS）表达的适应性增加，在天冬酰胺合成酶耐药细胞，这被认为是允许天冬酰胺合成酶耐药的人白血病细胞在体内存活。目前的结果，获得与ASNase敏感和耐药的人MOLT-4白血病细胞系，说明了几个其他的适应过程发生，以提供足够量的AS底物，天冬氨酸和谷氨酰胺，需要支持这种增加的酶活性。在这两种细胞群中，天冬氨酸几乎完全来自细胞内来源，而必需的谷氨酰胺来自细胞内和细胞外来源。与亲本细胞相比，谷氨酰胺转运到天冬氨酸酶抗性细胞中显著增强，而氨基酸流出（例如天冬酰胺）减少。大多数的适应性变化的氨基酸转运蛋白，系统A，ASC和L，是迅速（12小时）逆转后ASNase去除。谷氨酰胺合成酶的酶活性也通过转录后机制在天冬氨酸酶抗性细胞中增强。结果表明，在天冬氨酸酶处理的白血病细胞中存在几个代谢适应位点，其用于促进谷氨酰胺和天冬酰胺的补充。
Childhood acute lymphoblastic leukaemia is treated by combination chemotherapy with a number of drugs, almost always including the enzyme L-asparaginase (ASNase). Although the initial remission rate is quite high, relapse and associated drug resistance remain a problem. In vitro studies have demonstrated an adaptive increase in asparagine synthetase (AS) expression in ASNase-resistant cells, which is believed to permit ASNase-resistant human leukaemia cells to survive in vivo. The present results, obtained with ASNase-sensitive and -resistant human MOLT-4 leukaemia cell lines, illustrate that several other adaptive processes occur to provide sufficient amounts of the AS substrates, aspartate and glutamine, required to support this increased enzymic activity. In both cell populations, aspartate is derived almost exclusively from intracellular sources, whereas the necessary glutamine arises from both intracellular and extracellular sources. Transport of glutamine into ASNase-resistant cells is significantly enhanced compared with the parental cells, whereas amino acid efflux (e.g. asparagine) is reduced. Most of the adaptive change for the amino acid transporters, Systems A, ASC and L, is rapidly (12 h) reversed following ASNase removal. The enzymic activity of glutamine synthetase is also enhanced in ASNase-resistant cells by a posttranscriptional mechanism, The results demonstrate that there are several sites of metabolic adaptation in ASNase-treated leukaemia cells that serve to promote the replenishment of both glutamine and asparagine.