Su Nan, Pan Yuan-Xiang, Zhou Mi, Harvey Richard C, Hunger Stephen P, Kilberg Michael S
Department of Biochemistry and Molecular Biology, University of Florida Shands Cancer Center, University of Florida College of Medicine, Gainesville, Florida, USA.
Pediatr Blood Cancer. 2008 Feb;50(2):274-9. doi: 10.1002/pbc.21213.
Asparaginase (ASNase) is an essential component of most treatment protocols for childhood acute lymphoblastic leukemia (ALL). Although increased asparagine synthetase (ASNS) expression may contribute to ASNase resistance, there is conflicting data from patient samples with regard to correlation between ASNS mRNA content and ASNase sensitivity.
Both T-cell and B-cell derived ALL cell lines were treated with ASNase and then monitored for cell proliferation, cell death, and ASNS mRNA and protein expression.
Despite elevated ASNS mRNA following ASNase treatment, different ALL cell lines varied widely in translation to ASNS protein. Although ASNS mRNA levels did not consistently reflect ASNase sensitivity, there was an inverse correlation between ASNS protein and ASNase-induced cell death. Expression of ASNS in an ASNase-sensitive cell line resulted in enhanced ASNase resistance, and conversely, siRNA-mediated inhibition of ASNS expression promoted increased drug sensitivity.
These observations provide an explanation for the ASNase sensitivity of ALL cells and demonstrate the importance of measuring ASNS protein rather than mRNA in predicting ASNase responsiveness.
天冬酰胺酶（ASNase）是大多数儿童急性淋巴细胞白血病（ALL）治疗方案的重要组成部分。尽管天冬酰胺合成酶（ASNS）表达增加可能导致对ASNase产生耐药性，但来自患者样本的关于ASNS mRNA含量与ASNase敏感性之间相关性的数据存在矛盾。
T细胞和B细胞来源的ALL细胞系均用ASNase处理，然后监测细胞增殖、细胞死亡以及ASNS mRNA和蛋白表达。
尽管ASNase处理后ASNS mRNA升高，但不同的ALL细胞系在向ASNS蛋白的转化方面差异很大。虽然ASNS mRNA水平并不能始终反映ASNase敏感性，但ASNS蛋白与ASNase诱导的细胞死亡之间存在负相关。在ASNase敏感的细胞系中表达ASNS导致ASNase耐药性增强，相反，siRNA介导的ASNS表达抑制促进了药物敏感性增加。
这些观察结果解释了ALL细胞对ASNase的敏感性，并证明在预测ASNase反应性时测量ASNS蛋白而非mRNA的重要性。
