Scalaradial inhibition of epidermal growth factor receptor-mediated Akt phosphorylation is independent of secretory phospholipase A2.

The marine natural product 12-epi-scalaradial (SLD) is a specific secretory phospholipase A(2) (sPLA(2)) inhibitor. However, little is known about whether this compound has other pharmacological effects. Here, we revealed a novel effect of SLD on epidermal growth factor receptor (EGFR)-mediated Akt phosphorylation. SLD dose- and time-dependently inhibited epidermal growth factor (EGF)-stimulated Akt phosphorylation, which is required for Akt activation. SLD also blocked the EGF-stimulated membrane translocation of 3-phosphoinositide-dependent protein kinase 1 and inhibited phosphatidylinositol 3-kinase activity. This inhibition is specific for SLD because other phospholipase inhibitors, including sPLA(2) inhibitor thioetheramide-phosphatidylcholine, cytosolic PLA(2) inhibitor arachidonyl trifluoromethyl ketone, cytosolic PLA(2) and Ca(2+)-independent PLA(2) inhibitor methyl arachidonyl fluorophosphonate, phospholipase C inhibitor U73122, and cyclooxygenases inhibitor indomethacin, failed to inhibit EGF-stimulated Akt phosphorylation. Furthermore, arachidonic acid, the main sPLA(2)-catalyzed metabolite, was not able to rescue SLD inhibition of EGF-stimulated Akt phosphorylation. Overexpression of group IIA or group X sPLA(2) did not reverse the inhibitory effect of SLD on Akt phosphorylation, either. Our results demonstrate that SLD inhibits EGFR-mediated Akt phosphorylation, and this novel effect of SLD is independent of sPLA(2).