Characterization of human NSCLC cell line with innate etoposide-resistance mediated by cytoplasmic localization of topoisomerase II alpha
Characterization of human NSCLC cell line with innate etoposide-resistance mediated by cytoplasmic localization of topoisomerase II alpha
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DOI：
10.1111/j.1349-7006.2005.00111.x
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发表时间：
2005-11-01
期刊：
影响因子：
5.7
通讯作者：
Barrera-Rodríguez, R
中科院分区：
文献类型：
--
作者：
de Lucio, B;Manuel, V;Barrera-Rodríguez, R
拓扑异构酶(Topo)IIα是许多化疗药物临床应用的靶点。在对Topo II毒物耐药的肿瘤细胞中，已经有关于这种酶涉及的数量和质量变化的描述。最近，Topo IIα的细胞质定位被描述为一种赋予耐药的机制。在这里，我们报告了一种人类非小细胞肺癌细胞系INER-37的特征，它显示出对依托泊苷的先天耐药。在该细胞系中，依托泊苷耐药与Topo IIα的表达直接相关，Topo IIα主要位于细胞质区域。在分子水平上，INER-37细胞进行杂合性基因缺失，转录两种不同的Topo IIαmRNAs：4.8kb和2.0kb。较大的4.8kb的m RNA(缺失1.3 kb的3‘m RNA，包括非翻译区)被翻译成一个约160 kDa的截短的细胞质蛋白。蛋白质的截断影响到COOH-末端区域的至少96个氨基酸，该区域是更近端的两部分核定位信号所在的区域。INER-37细胞系是第一个报告了影响topo IIα基因趋势区的先天性突变的癌细胞株，这种突变使该酶在细胞质中定位，从而增加了对依托泊苷的耐药性。
Topoisomerase (topo) II alpha is a target for many chemotherapeutic agents in clinical use. In tumor cells resistant to topo II poisons, there have been descriptions of quantitative and qualitative alterations involved in this enzyme. More recently, the cytoplasmic localization of topo II alpha has been described as a mechanism to confer drug resistance. Here, we report the characterization of a human non-small-cell lung cancer cell line, INER-37, which shows an innate resistance to etoposide. in this cell line, etoposide resistance was directly associated with the expression of topo II alpha resident mainly in the cytoplasmic region. At the molecular level, INER-37 cells carry on a heterozygous gene deletion, transcribing two different topo II alpha mRNAs: 4.8 kb and 2.0 kb. The bigger 4.8 kb mRNA (missing 1.3 kb of 3' mRNA and including the untranslated region) is translated into a truncated cytoplasmic protein of approximately 160 kDa. The protein truncation affects at least 96 amino acids in the COOH-terminal region where the more proximal bipartite nuclear localization signal is located. The INER-37 cell line is the first cancer cell line reported with an innate mutation affecting the Tend region of the topo II alpha gene that confers a cytoplasmic localization of the enzyme and therefore an increased resistance to etoposide.