Electrophilic prostaglandins: identification of protein targets and opportunities for drug discovery

Electrophilic eicosanoids are endogenous mediators that play complex roles in signaling and adaptive responses. Basal generation of these species contributes to cell homeostasis, whereas their increased generation under situations of oxidative stress may contribute to cell adaptation or cytoprotection, and, if generated in amounts surpassing the cell detoxification mechanisms, may elicit cytotoxicity. Electrophilic prostaglandins with cyclopentenone structure (cyPG) have been shown to exert protective effects in numerous models of inflammation and tissue injury, as well as antitumoral effects. Protein covalent modification is a key mechanism of action of these species. We have used tagged electrophilic PG, mainly cyPG, as tools to characterize electrophilic lipid-protein interactomes. cyPG with different structure elicit the modification of subsets of proteins comprising both common and selective targets. Among the targets identified are proteins involved in inflammatory responses, the modification of which contributes to the anti-inflammatory effects of cyPG, signaling proteins, and proteins involved in chemoprevention, chemoresistance or tumorigenesis. Thus, some cyPG targets, including glutathione transferase and aldo-keto reductases, have broad implications both in redox signaling and as drug targets. We have observed that cyPG effects are highly dependent on cell type, context, and levels of both cyPG and endogenous antioxidants, in particular GSH. Moreover, the ability of cyPG to display biphasic or dual actions and the nature of the proteins modified depend on these factors. A detailed knowledge of cyPG targets and of the factors that modulate protein modification will contribute to the understanding of their mechanisms of action and define their potential as leads for drug discovery, but may also shed light on redox signaling mechanisms.

MINECO SAF2012-36519, ISCIII RD12/0013/0008 (Spain), EU COST Action CM1001.