Department of Biochemistry and Molecular and Cellular Biology, Georgetown University Medical Center, 3900 Reservoir Road NW, Washington, DC 20057, USA.
Mol Cancer Res. 2010 Dec;8(12):1656-64. doi: 10.1158/1541-7786.MCR-10-0342. Epub 2010 Nov 19.
The nonsteroidal anti-inflammatory drugs (NSAID) R-flurbiprofen and ibuprofen have been shown to induce expression of p75(NTR) (neurotrophin receptor) in prostate cancer cell lines. p75(NTR), a tumor necrosis factor receptor superfamily member, is a proapoptotic protein that functions as a tumor suppressor in the human prostate. Expression of p75(NTR) is lost as prostate cancer progresses and is minimal in several metastatic prostate cancer cell lines. NSAIDs induce p75(NTR) through activation of the p38 mitogen-activated protein kinase (MAPK) pathway, with a concomitant decrease in cell survival. Here, we show that treatment with R-flurbiprofen and ibuprofen induces expression of the NSAID-activated gene-1 (Nag-1) protein, a divergent member of the TGF beta (TGF-β) family, in PC-3 cells. Using the selective pharmacologic inhibitor of p38 MAPK, SB202190, and p38 MAPK-specific siRNA (small interfering RNA), we show that Nag-1 induction following NSAID treatment is mediated by the p38 MAPK pathway. p75(NTR)-specific siRNA pretreatment shows that Nag-1 induction by NSAIDs is downstream of p75(NTR) induction. Decreased survival of NSAID-treated cells is rescued by p75(NTR)-specific siRNA but not by Nag-1 siRNA. Transwell chamber and in vitro wound healing assays demonstrate decreased cell migration upon NSAID treatment. Pretreatment of PC-3 cells with p75(NTR) and Nag-1-specific siRNA shows that NSAID inhibition of cell migration is mediated by Nag-1 and p75(NTR). These results demonstrate a role for Nag-1 in NSAID inhibition of cell migration, but not survival.
非甾体类抗炎药（NSAID）R-氟比洛芬和布洛芬已被证明可诱导前列腺癌细胞系中 p75（NTR）（神经生长因子受体）的表达。p75（NTR）是肿瘤坏死因子受体超家族成员，是一种促凋亡蛋白，在人类前列腺中作为肿瘤抑制因子发挥作用。随着前列腺癌的进展，p75（NTR）的表达丢失，并且在几种转移性前列腺癌细胞系中很少。NSAIDs 通过激活 p38 丝裂原活化蛋白激酶（MAPK）途径诱导 p75（NTR）的表达，同时降低细胞存活率。在这里，我们表明，用 R-氟比洛芬和布洛芬处理可诱导 PC-3 细胞中 NSAID 激活基因-1（Nag-1）蛋白的表达，Nag-1 蛋白是 TGFβ（TGF-β）家族的一个不同成员。使用 p38 MAPK 的选择性药理抑制剂 SB202190 和 p38 MAPK 特异性 siRNA（小干扰 RNA），我们表明，NSAID 处理后 Nag-1 的诱导是通过 p38 MAPK 途径介导的。p75（NTR）特异性 siRNA 的预处理表明，NSAIDs 诱导的 Nag-1 诱导是 p75（NTR）诱导的下游。NSAID 处理的细胞存活率降低可通过 p75（NTR）特异性 siRNA 而不是 Nag-1 siRNA 挽救。Transwell 室和体外伤口愈合测定表明，NSAID 处理后细胞迁移减少。用 p75（NTR）和 Nag-1 特异性 siRNA 预处理 PC-3 细胞表明，NSAID 抑制细胞迁移是由 Nag-1 和 p75（NTR）介导的。这些结果表明，Nag-1 在 NSAID 抑制细胞迁移中起作用，但不是生存。
