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.

journal_name

Mol Carcinog

journal_title

Molecular carcinogenesis

authors

Kim J,Shim M

doi

10.1002/mc.22458

subject

Has Abstract

pub_date

2016-12-01 00:00:00

pages

2156-2167

issue

12

eissn

0899-1987

issn

1098-2744

journal_volume

55

pub_type

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