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CELLULAR AND MOLECULAR

Scalaradial Inhibition of Epidermal Growth Factor Receptor-Mediated Akt Phosphorylation Is Independent of Secretory Phospholipase A₂

Shanghai Institute of Materia Medica, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai, China

The marine natural product 12-epi-scalaradial (SLD) is a specific secretory phospholipase A₂ (sPLA₂) 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 sPLA₂ inhibitor thioetheramide-phosphatidylcholine, cytosolic PLA₂ inhibitor arachidonyl trifluoromethyl ketone, cytosolic PLA₂ and Ca²⁺-independent PLA₂ inhibitor methyl arachidonyl fluorophosphonate, phospholipase C inhibitor U73122, and cyclooxygenases inhibitor indomethacin, failed to inhibit EGF-stimulated Akt phosphorylation. Furthermore, arachidonic acid, the main sPLA₂-catalyzed metabolite, was not able to rescue SLD inhibition of EGF-stimulated Akt phosphorylation. Overexpression of group IIA or group X sPLA₂ 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 sPLA₂.

Address correspondence to: Dr. Liguang Lou, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China. E-mail: lglou{at}mail.shcnc.ac.cn