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首页> 外文期刊>BMC Medical Genomics >Role of Caveolin 1, E-Cadherin, Enolase 2 and PKCalpha on resistance to methotrexate in human HT29 colon cancer cells
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Role of Caveolin 1, E-Cadherin, Enolase 2 and PKCalpha on resistance to methotrexate in human HT29 colon cancer cells

机译：小窝蛋白1，E-钙黏着蛋白，烯醇酶2和PKCalpha对人HT29结肠癌细胞对甲氨蝶呤的抗性的作用

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Background Methotrexate is one of the earliest cytotoxic drugs used in cancer therapy, and despite the isolation of multiple other folate antagonists, methotrexate maintains its significant role as a treatment for different types of cancer and other disorders. The usefulness of treatment with methotrexate is limited by the development of drug resistance, which may be acquired through different ways. To get insights into the mechanisms associated with drug resistance and sensitization we performed a functional analysis of genes deregulated in methotrexate resistant cells, either due to its co-amplification with the dhfr gene or as a result of a transcriptome screening using microarrays. Methods Gene expression levels were compared between triplicate samples from either HT29 sensitive cells and resistant to 10-5 M MTX by hybridization to the GeneChip? HG U133 PLUS 2.0 from Affymetrix. After normalization, a list of 3-fold differentially expressed genes with a p-value Results Genes adjacent to the dhfr locus and included in the 5q14 amplicon were overexpressed in HT29 MTX-resistant cells. Treatment with siRNAs against those genes caused a slight reduction in cell viability in both HT29 sensitive and resistant cells. On the other hand, microarray analysis of HT29 and HT29 MTX resistant cells unveiled overexpression of caveolin 1, enolase 2 and PKCα genes in resistant cells without concomitant copy number gain. siRNAs against these three genes effectively reduced cell viability and caused a decreased MTX resistance capacity. Moreover, overexpression of E-cadherin, which was found underexpressed in MTX-resistant cells, also sensitized the cells toward the chemotherapeutic agent. Combined treatments targeting siRNA inhibition of caveolin 1 and overexpression of E-cadherin markedly reduced cell viability in both sensitive and MTX-resistant HT29 cells. Conclusion We provide functional evidences indicating that caveolin 1 and E-cadherin, deregulated in MTX resistant cells, may play a critical role in cell survival and may constitute potential targets for coadjuvant therapy.
机译：背景技术甲氨蝶呤是用于癌症治疗的最早的细胞毒性药物之一，尽管已分离出多种其他叶酸拮抗剂，但氨甲蝶呤在治疗不同类型的癌症和其他疾病方面仍保持着重要的作用。甲氨蝶呤治疗的有用性受到耐药性发展的限制，这可以通过不同的方式获得。为了深入了解与药物耐药性和致敏性相关的机制，我们对甲氨蝶呤耐药细胞中失控的基因进行了功能分析，这可能是由于其与dhfr基因的共同扩增，或者是使用微阵列筛选转录组的结果。方法通过与Affymetrix公司的GeneChip ？ HG U133 PLUS 2.0杂交，比较HT29敏感细胞和三份对10 -5 M MTX有抗性的样品的基因表达水平。标准化后，与dhfr基因座相邻并包含在5q14扩增子中的p值为3的差异表达基因列表在HT29 MTX抗性细胞中过表达。针对这些基因的siRNA处理导致HT29敏感和耐药细胞的细胞活力略有下降。另一方面，对HT29和HT29 MTX抗性细胞的微阵列分析揭示了抗性细胞中小窝蛋白1，烯醇酶2和PKCα基因的过表达，而没有增加拷贝数。针对这三个基因的siRNA有效降低了细胞活力，并导致MTX抗性降低。此外，在MTX抗性细胞中发现表达不足的E-钙粘着蛋白也使细胞对化学治疗剂敏感。针对siRNA抑制小窝蛋白1和E-钙粘蛋白过度表达的联合治疗显着降低了敏感性和耐MTX HT29细胞的细胞活力。结论我们提供的功能性证据表明，在MTX耐药细胞中失活的小窝蛋白1和E-钙粘蛋白可能在细胞存活中起关键作用，并可能构成辅助治疗的潜在靶标。

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