NSAID inhibition of prostate cancer cell migration is mediated by Nag-1 induction via the p38 MAPK-p75NTR pathway

Abstract

The nonsteroidal anti-inflammatory drugs (NSAID) R-flurbiprofen and ibuprofen have been shown to induce expression of p75NTR (neurotrophin receptor) in prostate cancer cell lines. p75NTR, a tumor necrosis factor receptor superfamily member, is a proapoptotic protein that functions as a tumor suppressor in the human prostate. Expression of p75NTR is lost as prostate cancer progresses and is minimal in several metastatic prostate cancer cell lines. NSAIDs induce p75NTR 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 p75NTR induction. Decreased survival of NSAID-treated cells is rescued by p75NTRspecific 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 p75NTR and Nag-1-specific siRNA shows that NSAID inhibition of cell migration is mediated by Nag-1 and p75NTR. These results demonstrate a role for Nag-1 in NSAID inhibition of cell migration, but not survival. ©2010 AACR.