The transcription factor GCF2 is an upstream repressor of the small GTPAse RhoA, regulating membrane protein trafficking, sensitivity to doxorubicin, and resistance to cisplatin.
The transcription factor GCF2 is an upstream repressor of the small GTPAse RhoA, regulating membrane protein trafficking, sensitivity to doxorubicin, and resistance to cisplatin.
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DOI：
10.1021/mp300153z
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发表时间：
2012-06-04
影响因子：
4.9
通讯作者：
Gottesman MM
中科院分区：
文献类型：
--
作者：
Shen DW;Pouliot LM;Gillet JP;Ma W;Johnson AC;Hall MD;Gottesman MM
我们的目的是探索转录抑制因子 GCF2 在 RhoA 沉默、细胞骨架解体、MRP1 错误定位以及作为癌症治疗上游基因靶标的抗癌药物敏感性中的作用。在人顺铂耐药细胞中发现 GCF2 表达增加，GCF2 转染细胞中的过度表达会导致 RhoA 表达丧失和肌动蛋白-细丝蛋白网络破坏。结果，膜转运蛋白 MRP1 从细胞表面内化到细胞质中，由于细胞内阿霉素积累增加，使细胞对阿霉素的敏感性提高 10 倍以上。 GCF2转染子还表现出顺铂积累减少和耐药性增加。靶向GCF2的siRNA抑制顺铂耐药细胞中GCF2的表达，重新激活RhoA表达，并恢复肌动蛋白微丝的精细结构。 MRP1也被重新定位到细胞表面。靶向 RhoA 的 siRNA 使 KB-3-1 和 KB-CP.5 细胞的耐药性增加了 3 倍。这些数据首次证明了 GCF2 下游的一种新颖的复杂调控途径，涉及小 GTP 酶 RhoA、肌动蛋白/丝蛋白动力学和膜蛋白运输。该途径介导对细胞毒性化合物的多种反应，并且还为进一步研究顺铂耐药细胞中发挥作用的多效性耐药机制提供分子基础。
Our aim was to explore the involvement of the transcriptional suppressor GCF2 in silencing RhoA, disorganization of the cytoskeleton, mislocalization of MRP1, and sensitivity to anti-cancer agents as an upstream gene target in cancer therapy. Increased expression of GCF2 was found in human cisplatin-resistant cells, and overexpression in GCF2-transfected cells results in loss of RhoA expression and disruption of the actin-filamin network. In consequence, the membrane transporter MRP1 was internalized from the cell surface into the cytoplasm, rendering cells sensitive to doxorubicin by more than 10-fold due to increased accumulation of doxorubicin in the cells. The GCF2 transfectants also showed reduced accumulation of cisplatin and increased resistance. siRNA targeted to GCF2 suppressed the expression of GCF2 in cisplatin-resistant cells, re-activated RhoA expression, and restored the fine structure of actin microfilaments. MRP1 was also relocated to the cell surface. siRNA targeted to RhoA increased resistance 3-fold in KB-3-1 and KB-CP.5 cells. These data for the first time demonstrate a novel complex regulatory pathway downstream from GCF2 involving the small GTPase RhoA, actin/filamin dynamics, and membrane protein trafficking. This pathway mediates diverse responses to cytotoxic compounds, and also provides a molecular basis for further investigation into the pleiotropic resistance mechanism at play in cisplatin-resistant cells.
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