Alteration in copy numbers of genes as a mechanism for acquired drug resistance
Alteration in copy numbers of genes as a mechanism for acquired drug resistance
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DOI：
10.1158/0008-5472.can-3263-2
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发表时间：
2004-02-15
期刊：
影响因子：
11.2
通讯作者：
Inazawa, J
中科院分区：
文献类型：
--
作者：
Yasui, K;Mihara, S;Inazawa, J
化学抗性是癌症成功治疗的主要障碍。为了确定与治疗药物获得性耐药相关的基因组区域，我们对23种癌细胞系进行了分子细胞遗传学分析，每种癌细胞系对喜树碱、顺铂、依托泊苷（VP-16）、阿霉素或1-β-D-阿拉伯呋喃糖基胞嘧啶都有耐药，尽管亲本肿瘤细胞系没有耐药。减法比较基因组杂交研究揭示了耐药细胞系特征性的DNA拷贝数增加或减少的区域;即，与其药物敏感的亲本细胞系的差异。在检测的19个耐药细胞系中扩增了13个ATP结合盒（ABC）转运蛋白基因[ABCA 3、ABCB 1（MDR 1）、ABCB 6、ABCB 8、ABCB 10、ABCB 11、ABCC 1（MRP 1）、ABCC 4、ABCC 9、ABCD 3、ABCD 4、ABCE 1和ABCF 2]。编码抗凋亡BCL-2蛋白的三个基因（BCL 2L 2、MCL 1和BCL 2L 10）也被扩增，因此在三个衍生系中过表达。用反义寡核苷酸下调BCL 2L 2使VP-16抗性卵巢癌细胞系（SKOV 3/VP）对VP-16敏感。脱氧胞苷激酶、DNA拓扑异构酶I和DNA拓扑异构酶II α编码基因拷贝数的减少分别降低了一个阿糖胞苷耐药株系、三个喜树碱耐药株系中的两个和五个VP-16耐药细胞系中的两个的表达水平。我们的研究结果表明，上述基因的DNA拷贝数的变化可以激活或下调它们在耐药细胞系中，这种基因组改变可能与获得性耐药性有关。
Chemoresistance is a major obstacle for successful treatment of cancer. To identify regions of the genome associated with acquired resistance to therapeutic drugs, we conducted molecular cytogenetic analyses of 23 cancer-cell lines, each resistant to either camptothecin, cisplatin, etoposide (VP-16), Adriamycin, or 1-beta-D-arabinofuranosylcytosine, although the parental tumor lines were not. Subtractive comparative genomic hybridization studies revealed regions of gain or loss in DNA-copy numbers that were characteristic of drug-resistant cell lines; i.e., differences from their drug-sensitive parental cell lines. Thirteen ATP-binding cassette (ABC) transporter genes [ABCA3, ABCB1 (MDR1), ABCB6, ABCB8, ABCB10, ABCB11, ABCC1 (MRP1), ABCC4, ABCC9, ABCD3, ABCD4, ABCE1, and ABCF2] were amplified among 19 of the resistant cell lines examined. Three genes encoding antiapoptotic BCL-2 proteins (BCL2L2, MCL1, and BCL2L10) were also amplified and consequently overexpressed in three of the derivative lines. Down-regulation of BCL2L2 with an antisense oligonucleotide sensitized a VP-16 resistant ovarian-cancer cell line (SKOV3/VP) to VP-16. A decrease in copy numbers of genes encoding deoxycytidine kinase, DNA topoisomerase I, and DNA topoisomerase II alpha reduced their expression levels in one cytosine arabinoside-resistant line, two of three camptothecin-resistant lines, and two of five VP-16-resistant cell lines, respectively. Our results indicated that changes in DNA-copy numbers of the genes mentioned can activate or down-regulate them in drug-resistant cell lines, and that such genomic alterations might be implicated in acquired chemoresistance.