The p38 MAPK pathway mediates aryl propionic acid induced messenger rna stability of p75 NTR in prostate cancer cells.
The p38 MAPK pathway mediates aryl propionic acid induced messenger rna stability of p75 NTR in prostate cancer cells.
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p38 MAPK 途径介导前列腺癌细胞中芳基丙酸诱导的 p75 NTR 信使 RNA 稳定性。
DOI：
10.1158/0008-5472.can-07-1792
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发表时间：
2007
期刊：
影响因子：
11.2
通讯作者：
Djakiew,Daniel
中科院分区：
文献类型：
--
作者：
Quann,EmilyJ;Khwaja,Fatima;Djakiew,Daniel
p75NTR在前列腺中作为肿瘤抑制因子，但其表达随着前列腺癌的进展而丧失，并且在已建立的前列腺癌细胞系如PC-3、DU-145和LNCaP中是最小的。以前，我们发现用R-氟比洛芬或布洛芬处理诱导PC-3和DU-145细胞中p75NTR的表达，导致p75NTR介导的存活率降低。在这里，我们研究这些药物诱导p75NTR表达的机制。我们发现，由于R-氟比洛芬和布洛芬治疗所观察到的p75NTR蛋白的增加伴随着p75NTR mRNA的增加，这种mRNA的增加是mRNA稳定性增加的结果，而不是转录上调。此外，我们表明，治疗与R-氟比洛芬或布洛芬导致持续激活的p38丝裂原活化蛋白激酶（MAPK）途径。此外，用p38 MAPK特异性抑制剂SB 202190或通过小干扰RNA（siRNA）敲低p38 MAPK蛋白来抑制p38 MAPK途径，可防止R-氟比洛芬和布洛芬诱导p75 NTR。我们还观察到，MAPK活化蛋白激酶（MK）-2和MK3的siRNA敲低，p38 MAPK下游的激酶，负责p38 MAPK途径的mRNA稳定作用，也阻止了诱导p75 NTR的R-氟比洛芬和布洛芬。最后，我们确定的RNA稳定蛋白HuR和转录后调节真核生物翻译起始因子4E作为两种可能的机制，p38 MAPK途径可能会增加p75 NTR的表达。总的来说，这些数据表明，R-氟比洛芬和布洛芬诱导p75NTR的表达增加的mRNA的稳定性，介导的p38 MAPK途径。[Cancer Res 2007; 67（23）：11402 - 10]
The p75NTRacts as a tumor suppressor in the prostate, but its expression is lost as prostate cancer progresses and is minimal in established prostate cancer cell lines such as PC-3, DU-145, and LNCaP. Previously, we showed that treatment with R-flurbiprofen or ibuprofen induced p75NTRexpression in PC-3 and DU-145 cells leading to p75NTR-mediated decreased survival. Here, we investigate the mechanism by which these drugs induce p75NTRexpression. We show that the observed increase in p75NTRprotein due to R-flurbiprofen and ibuprofen treatment was accompanied by an increase in p75NTRmRNA, and this increase in mRNA was the result of increased mRNA stability and not by an up-regulation of transcription. In addition, we show that treatment with R-flurbiprofen or ibuprofen led to sustained activation of the p38 mitogen-activated protein kinase (MAPK) pathway. Furthermore, inhibition of the p38 MAPK pathway with the p38 MAPK–specific inhibitor SB202190 or by small interfering RNA (siRNA) knockdown of p38 MAPK protein prevented induction of p75NTRby R-flurbiprofen and ibuprofen. We also observed that siRNA knockdown of MAPK-activated protein kinase (MK)-2 and MK3, the kinases downstream of p38 MAPK that are responsible for the mRNA stabilizing effects of the p38 MAPK pathway, also prevented an induction of p75NTRby R-flurbiprofen and ibuprofen. Finally, we identify the RNA stabilizing protein HuR and the posttranscriptional regulator eukaryotic translation initiation factor 4E as two possible mechanisms by which the p38 MAPK pathway may increase p75NTRexpression. Collectively, the data suggest that R-flurbiprofen and ibuprofen induce p75NTRexpression by increased mRNA stability that is mediated through the p38 MAPK pathway. [Cancer Res 2007;67(23):11402–10]