卵巢癌细胞对顺铂、紫杉醇或阿霉素耐药性的基因表达和通路分析。
Gene expression and pathway analysis of ovarian cancer cells selected for resistance to cisplatin, paclitaxel, or doxorubicin.
机构信息
Laboratory of Molecular Biology and Immunology, National Institute on Aging, Baltimore MD 21224, USA.
出版信息
J Ovarian Res. 2011 Dec 5;4(1):21. doi: 10.1186/1757-2215-4-21.
BACKGROUND
Resistance to current chemotherapeutic agents is a major cause of therapy failure in ovarian cancer patients, but the exact mechanisms leading to the development of drug resistance remain unclear.
METHODS
To better understand mechanisms of drug resistance, and possibly identify novel targets for therapy, we generated a series of drug resistant ovarian cancer cell lines through repeated exposure to three chemotherapeutic drugs (cisplatin, doxorubicin, or paclitaxel), and identified changes in gene expression patterns using Illumina whole-genome expression microarrays. Validation of selected genes was performed by RT-PCR and immunoblotting. Pathway enrichment analysis using the KEGG, GO, and Reactome databases was performed to identify pathways that may be important in each drug resistance phenotype.
RESULTS
A total of 845 genes (p < 0.01) were found altered in at least one drug resistance phenotype when compared to the parental, drug sensitive cell line. Focusing on each resistance phenotype individually, we identified 460, 366, and 337 genes significantly altered in cells resistant to cisplatin, doxorubicin, and paclitaxel, respectively. Of the 845 genes found altered, only 62 genes were simultaneously altered in all three resistance phenotypes. Using pathway analysis, we found many pathways enriched for each resistance phenotype, but some dominant pathways emerged. The dominant pathways included signaling from the cell surface and cell movement for cisplatin resistance, proteasome regulation and steroid biosynthesis for doxorubicin resistance, and control of translation and oxidative stress for paclitaxel resistance.
CONCLUSIONS
Ovarian cancer cells develop drug resistance through different pathways depending on the drug used in the generation of chemoresistance. A better understanding of these mechanisms may lead to the development of novel strategies to circumvent the problem of drug resistance.
背景
目前化疗药物的耐药性是卵巢癌患者治疗失败的主要原因，但导致耐药性发展的确切机制仍不清楚。
方法
为了更好地了解耐药机制，并可能为治疗找到新的靶点，我们通过反复暴露于三种化疗药物（顺铂、多柔比星或紫杉醇）来生成一系列耐药卵巢癌细胞系，并使用 Illumina 全基因组表达微阵列来识别基因表达模式的变化。通过 RT-PCR 和免疫印迹验证了选定基因的表达。使用 KEGG、GO 和 Reactome 数据库进行通路富集分析，以鉴定在每种耐药表型中可能重要的通路。
结果
与亲本、药物敏感细胞系相比，至少一种耐药表型中共有 845 个基因（p<0.01）发生改变。分别针对每种耐药表型进行重点研究，我们发现，对顺铂、多柔比星和紫杉醇耐药的细胞中分别有 460、366 和 337 个基因发生显著改变。在 845 个改变的基因中，只有 62 个基因同时在三种耐药表型中发生改变。通过通路分析，我们发现每种耐药表型都有许多通路富集，但也出现了一些主要通路。主要通路包括细胞表面信号和细胞运动与顺铂耐药有关，蛋白酶体调节和类固醇生物合成与多柔比星耐药有关，翻译和氧化应激控制与紫杉醇耐药有关。
结论
卵巢癌细胞通过不同的通路产生耐药性，具体取决于用于产生化疗耐药性的药物。更好地了解这些机制可能会导致开发出规避耐药问题的新策略。
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