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

We investigated the effects of prostaglandin E(2) (PGE(2)), 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(2) (−.)) formation, PGE(2) 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(2) also abolished the DNA-damaging effects of arsenite and that this response was associated with an unexpected suppression of mitoO(2) (−.) formation. We conclude that PGE(2) promotes PKA-dependent inhibition of mitoO(2) (−.) 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(2) (−.) formation, PGE(2) fails to enhance—but rather decreases—the risk of neoplastic transformation associated with genotoxic events.