title: COX-2 inhibitor NS-398 suppresses doxorubicin-induced p53 accumulation through inhibition of ROS-mediated Jnk activation.
abstract: Cyclooxygenase-2 (COX-2) is one of the isoforms of cyclooxygenase, a rate-limiting enzyme in the arachidonic acid cascade. COX-2 protein expression is highly induced by numerous factors and it has been reportedly overexpressed in various human malignancies. Although anti-tumorigenic effects of COX-2 inhibitors have been shown, several lines of evidence suggest that COX-2 inhibitors antagonize the cytotoxicity of chemotherapeutic agents. In this study, we investigated the effect of NS-398, a COX-2 inhibitor, on modulation of doxorubicin (DOX)-induced p53 accumulation. Non-selective and selective COX-2 inhibitors attenuated DOX-induced accumulation of wild type (WT) but not mutant p53. Nutlin-3α or MG132 abolished the suppressive effect of a COX-2 inhibitor on DOX-induced p53 increase. Moreover, the DOX-induced increase in p53 protein levels was reduced in COX-2 knockout (KO) mouse embryonic fibroblasts (MEFs) compared to those in WT or COX-1 KO MEFs. DOX-induced accumulation of p53 was attenuated by a specific inhibitor or knockdown of Jun-N-terminal kinase (Jnk). In addition, DOX-induced Jnk activation was decreased in COX-2 KO MEFs or by COX-2 inhibition, suggesting that Jnk stabilizes p53 by a mechanism that involves COX-2. Pre-treatment with a reactive oxygen species (ROS) scavenger, N-acetylcysteine, attenuated DOX-induced Jnk activation and subsequent p53 accumulation. Furthermore, the absence or inhibition of COX-2 resulted in suppression of DOX-induced increase in ROS levels. These results suggest that COX-2 activates Jnk through modulation of ROS levels, leading to accumulation of p53. Our study identifies a putative novel cross-talk between COX-2 and p53. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Biological Sciences, University of South Carolina, Columbia, South Carolina.|Center for Colon Cancer Research, University of South Carolina, Columbia, South Carolina.
authors.forename: Joohwee
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Biological Sciences, University of South Carolina, Columbia, South Carolina.|Center for Colon Cancer Research, University of South Carolina, Columbia, South Carolina.
authors.forename: Minsub
authors.initials: M
authors.lastname: Shim
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D004317:Doxorubicin / Q000494:pharmacology*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D009578:Nitrobenzenes / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D052246:Cyclooxygenase 2 Inhibitors; D009578:Nitrobenzenes; D017382:Reactive Oxygen Species; D013449:Sulfonamides; D016159:Tumor Suppressor Protein p53; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D004317:Doxorubicin; D048031:JNK Mitogen-Activated Protein Kinases
keywords: Jun-N-terminal kinase; TP53; cyclooxygenase-2; doxorubicin; reactive oxygen species