Cisplatin-resistance modulates the effect of protein synthesis inhibitors on spermidine/spermine N1-acetyltransferase expression
Cisplatin-resistance modulates the effect of protein synthesis inhibitors on spermidine/spermine N1-acetyltransferase expression
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DOI：
10.1016/s1357-2725(03)00174-2
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发表时间：
2004-01-01
影响因子：
4
通讯作者：
Moruzzi, MS
中科院分区：
文献类型：
--
作者：
Marverti, G;Monti, MG;Moruzzi, MS
顺铂（DDP）耐药的人卵巢癌细胞系（C13*）在精胺类似物n - 1，n -12-双（乙基）精胺（BESpm）的作用下，与亲代DDP敏感的2008细胞相比，亚精胺/精胺N-1乙酰转移酶（SSAT）基因表达不足。这种SSAT基因缺陷与对精胺类似物的生长敏感性降低有关。本研究旨在确定抗性细胞的SSAT基因表达是否受到抗性选择过程中产生的不稳定抑制蛋白的抑制。本研究表明，在2008年和C13*细胞中，环己亚胺（CHX）和大霉素（ANISO）的抑制浓度对bespm诱导的SSAT活性有不同的影响，并以浓度依赖的方式使耐药细胞达到与敏感细胞相当的激活水平。Northern blot分析显示，CHX和ANISO联合BESpm均可在C13*细胞中引起BESpm介导的SSAT mRNA的协同积累，而在2008细胞中仅观察到轻微的增加。抑制剂对BESpm在抗性细胞中诱导的SSAT活性的影响更为明显，也是SSAT mRNA和酶蛋白稳定时间更长的结果。相比之下，CHX和ANISO的亚抑制浓度没有显著刺激bespm诱导的SSAT转录和活性。这些结果表明，与ddp抗性表型相关的不稳定抑制蛋白在SSAT基因表达中发挥调节作用，并进一步表明克服这种抑制控制有可能恢复BESpm应答。(C) 2003 Elsevier Ltd.版权所有。
Cisplatin (DDP)-resistance confers a deficient expression of spermidine/spermine N-1-acetyltransferase (SSAT) gene in response to the spermine analog N-1,N-12-bis(ethyl)spermine (BESpm) in the DDP-resistant human ovarian carcinoma cell line (C13*), compared with their parental DDP-sensitive 2008 cells. This SSAT gene deficiency is correlated with a reduced growth sensitivity to spermine analogs. This study was performed to determine whether SSAT gene expression of resistant cells was kept suppressed by labile repressor proteins developed during resistance selection. We show here that inhibitory concentrations of cycloheximide (CHX) and anisomycin (ANISO) differentially affect BESpm-induced SSAT activity in 2008 and in C13* cells in a concentration-dependent manner and allow resistant cells to reach activation levels comparable to those of the sensitive cells. Northern blot analysis revealed that both CHX and ANISO in combination with BESpm caused a synergistic BESpm-mediated accumulation of SSAT mRNA in C13* cells, with respect to each drug alone, while in 2008 cells only a slight increase was observed. The more pronounced effect of inhibitors on the SSAT activity induced by BESpm in the resistant cells was also the result of a more prolonged stabilization of SSAT mRNA and enzyme protein. By contrast, sub-inhibitory concentrations of CHX and ANISO did not significantly stimulate BESpm-induced SSAT transcription and activity. These results suggest that labile repressor proteins, related to DDP-resistance phenotype, play a regulatory role in SSAT gene expression, and further indicate that by overcoming this inhibitory control it is possible to recover BESpm response. (C) 2003 Elsevier Ltd. All rights reserved.