Abstract 1263: Induction of nonsteroidal anti-inflammatory drug-activated gene-1 (Nag-1) by NSAIDs: role of p75NTR

Abstract

Abstract Epidemiologic studies have shown that patients with long term consumption of certain nonsteroidal anti-inflammatory drugs (NSAIDs) exhibit a reduced incidence of prostate cancer. Treatment of prostrate cancer cell lines with NSAIDs leads to caspase mediated apoptosis. Previously, our laboratory has demonstrated that R-flurbiprofen and Ibuprofen induce the expression of the pro-apoptotic protein p75NTR in PC-3, DU-145 and LNCaP prostate cancer cell lines, with a subsequent decrease in cell survival. The p75NTR is a member of the Tumor Necrosis Factor Receptor superfamily of death receptors. It acts as a tumor suppressor in the normal prostate. The expression of p75NTR is lost as prostate cancer progresses and is minimal in established metastatic prostate cancer cell lines such as PC-3, DU-145, and LNCaP. The observed increase in p75NTR protein due to R-flurbiprofen and Ibuprofen treatment occurs as a result of activation of the p38 mitogen-activated protein kinase (MAPK) pathway. Here we show that the upregulation of p75NTR following treatment with NSAIDs corresponds to a concomitant upregulation of the NSAID activated gene-1 (Nag-1) protein, a pro-apoptotic member of the TGF beta family, in PC-3 cells. Nag-1 has been linked to decreased cell proliferation in many studies, and has been shown to play a pro-apoptotic role in breast, colorectal, gastric and prostate cancer cells. Nag-1 is also known by the names GDF −15, MIC-1, PDF, PLAB and PTGFB. This study also shows that Nag-1 protein induction following NSAID treatment is mediated by the p38 MAPK pathway, and is downstream of the p75NTR induction. This is the first report of a relationship between p75NTR and Nag-1. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1263.