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).
Xie
Yili
Y
Shanghai Institute of Materia Medica, Chinese Academy of Sciences.
Liu
Lunhua
L
Huang
Xiaochun
X
Guo
Yuewei
Y
Lou
Liguang
L
D064413:3-Phosphoinositide-Dependent Protein Kinases; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D054501:Group II Phospholipases A2; D006718:Homosteroids / Q000494:pharmacology*; D006801:Humans; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010741:Phospholipases A / Q000037:antagonists & inhibitors* / Q000502:physiology*; D054467:Phospholipases A2; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D054830:Sesterterpenes; D013729:Terpenes / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D006718:Homosteroids; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D054830:Sesterterpenes; D013729:Terpenes; C071197:scalaradial; D066246:ErbB Receptors; D064413:3-Phosphoinositide-Dependent Protein Kinases; C494918:AKT1 protein, human; C578562:PDPK1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D010741:Phospholipases A; D054501:Group II Phospholipases A2; D054467:Phospholipases A2