AUTHOR=Cerioni Liana , Guidarelli Andrea , Fiorani Mara , Cantoni Orazio 

TITLE=Prostaglandin E2 Signals Through E Prostanoid Receptor 2 to Inhibit Mitochondrial Superoxide Formation and the Ensuing Downstream Cytotoxic and Genotoxic Effects Induced by Arsenite

JOURNAL=Frontiers in Pharmacology

VOLUME=10

YEAR=2019

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2019.00781

DOI=10.3389/fphar.2019.00781

ISSN=1663-9812

ABSTRACT=<p>We investigated the effects of prostaglandin E<sub>2</sub> (PGE<sub>2</sub>), an important inflammatory lipid mediator, on the cytotoxicity–genotoxicity induced by arsenite. With the use of a toxicity paradigm in which the metalloid uniquely induces mitochondrial superoxide (mitoO<sub>2</sub><sup>−.</sup>) formation, PGE<sub>2</sub> promoted conditions favoring the cytosolic accumulation of Bad and Bax and abolished mitochondrial permeability transition (MPT) and the ensuing lethal response through an E prostanoid receptor 2/adenylyl cyclase/protein kinase A (PKA) dependent signaling. It was, however, interesting to observe that, under the same conditions, PGE<sub>2</sub> also abolished the DNA-damaging effects of arsenite and that this response was associated with an unexpected suppression of mitoO<sub>2</sub><sup>−.</sup> formation. We conclude that PGE<sub>2</sub> promotes PKA-dependent inhibition of mitoO<sub>2</sub><sup>−.</sup> formation, thereby blunting the downstream responses mediated by these species, leading to DNA strand scission and MPT-dependent apoptosis. These findings are therefore consistent with the possibility that, in cells responding to arsenite with mitoO<sub>2</sub><sup>−.</sup> formation, PGE<sub>2</sub> fails to enhance—but rather decreases—the risk of neoplastic transformation associated with genotoxic events.</p>