Abstract
We investigated the effects of prostaglandin E2 (PGE2), 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 (mitoO2 −.) formation, PGE2 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, PGE2 also abolished the DNA-damaging effects of arsenite and that this response was associated with an unexpected suppression of mitoO2 −. formation. We conclude that PGE2 promotes PKA-dependent inhibition of mitoO2 −. 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 mitoO2 −. formation, PGE2 fails to enhance—but rather decreases—the risk of neoplastic transformation associated with genotoxic events.
Highlights
Arsenite is a widely distributed environmental toxicant causing an increased incidence of various pathologies and forms of cancer in numerous parts of the planet (Flora, 2011; Shakoor et al, 2017; Minatel et al, 2018)
We report that the effects of catalase are mimicked by rotenone, an inhibitor of complex I (Degli Esposti, 1998) preventing mitoO2−. formation induced by arsenite (Guidarelli et al, 2016a), and that KT5720 fails to affect the DNA-damaging response induced by arsenite alone or combined with any of the above treatments (Figure 4A)
The present study was undertaken to determine the effects of prostaglandin E2 (PGE2) on arsenite cytotoxicity–genotoxicity, with the purpose of identifying responses with a potential impact on the carcinogenicity of the metalloid
Summary
Arsenite is a widely distributed environmental toxicant causing an increased incidence of various pathologies and forms of cancer in numerous parts of the planet (Flora, 2011; Shakoor et al, 2017; Minatel et al, 2018). Was identified as the critical upstream species indirectly responsible, i.e., through the intermediate formation of H2O2, for the triggering of events associated with vicinal effects culminating in mitochondrial dysfunction/permeability transition (MPT) (Guidarelli et al, 2016a; Fiorani et al, 2018), as well as distal effects, which include the formation of lesions at the level of genomic DNA (Guidarelli et al, 2017). All these effects were followed by a delayed (i.e., after 24–48 h) apoptotic response, restricted to a small proportion of cells (Guidarelli et al, 2016a; Guidarelli et al, 2016b; Guidarelli et al, 2017)
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