MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center and the School of Medicine, Nanjing University, Nanjing, China.
Biomed Pharmacother. 2013 Apr;67(3):197-202. doi: 10.1016/j.biopha.2013.01.001. Epub 2013 Feb 1.
The multidrug resistance 1 (MDR1) gene product P-glycoprotein is an ATP-dependent efflux pump associated with chemotherapy failure in breast cancer. In the present study, we show that paclitaxel induces MDR1 expression in the MCF-7 breast cancer cell line in a MAPK/Egr-1-dependent manner. Paclitaxel exposure activated the Erk1/2/MAPK pathway and promoted the accumulation of the early response transcription factor Egr-1 in MCF-7 cells. Egr-1 binds to the GC element on the proximal MDR1 promoter to enhance MDR1 transcription. Loss of Egr-1 function in paclitaxel-resistant MCF-7 cells decreased MDR1 expression, whereas inhibiting Erk1/2 activity reduced both Egr-1 accumulation and MDR1 expression. These findings suggest that Erk1/2-induced Egr-1 accumulation activates MDR1 transcription and thereby induces the drug resistance observed in paclitaxel-resistant MCF-7 cells. Further mechanistic studies indicate that Egr-1 most likely does not induce the constitutive activation of Erk1/2 through its target gene geranylgeranyl diphosphate synthase (GGPPS), which regulates Ras prenylation. Indeed, our results suggest a novel pathway by which paclitaxel induces MDR1 expression, possibly illuminating a potential target pathway for the prevention of MDR1-mediated drug resistance.
多药耐药 1（MDR1）基因产物 P-糖蛋白是一种与乳腺癌化疗失败相关的 ATP 依赖性外排泵。在本研究中，我们表明紫杉醇以依赖 MAPK/Egr-1 的方式诱导 MCF-7 乳腺癌细胞系中 MDR1 的表达。紫杉醇暴露激活了 Erk1/2/MAPK 途径，并促进了早期反应转录因子 Egr-1 在 MCF-7 细胞中的积累。Egr-1 结合到近端 MDR1 启动子上的 GC 元件以增强 MDR1 转录。在紫杉醇耐药 MCF-7 细胞中丧失 Egr-1 功能会降低 MDR1 的表达，而抑制 Erk1/2 活性则会减少 Egr-1 的积累和 MDR1 的表达。这些发现表明，Erk1/2 诱导的 Egr-1 积累激活了 MDR1 转录，从而诱导了紫杉醇耐药 MCF-7 细胞中观察到的耐药性。进一步的机制研究表明，Egr-1 不太可能通过其靶基因香叶基香叶基二磷酸合酶（GGPPS）诱导 Erk1/2 的组成性激活，GGPPS 调节 Ras 异戊二烯化。事实上，我们的结果表明了紫杉醇诱导 MDR1 表达的新途径，可能为预防 MDR1 介导的耐药性提供了一个潜在的靶向途径。
