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COX‐2 inhibitor NS‐398 suppresses doxorubicin‐induced p53 accumulation through inhibition of ROS‐mediated Jnk activation
Author(s) -
Kim Joohwee,
Shim Minsub
Publication year - 2016
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/mc.22458
Subject(s) - biology , doxorubicin , reactive oxygen species , gene knockdown , microbiology and biotechnology , cancer research , pharmacology , apoptosis , biochemistry , genetics , chemotherapy
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.