Antiapoptotic Effect of Serum and Glucocorticoid-Inducible Protein Kinase Is Mediated by Novel Mechanism Activating IκB Kinase

Abstract

Abstract Serum and glucocorticoid inducible protein kinase (SGK) plays a crucial role in promoting cell survival, but the mechanisms for this response are not clear. We show that SGK is involved in the regulation of apoptosis in breast cancer cells by modulating the transcriptional activity of nuclear transcription factor κB (NF-κB). High levels of SGK expression were observed in human breast cancer samples. When SGK was reduced the apoptotic rate increased, and increased SGK activity prevents serum withdrawal–induced apoptosis. SGK-induced cell survival was abolished by a dominant-negative form of IκB kinase β (IKKβ, K44A) or a null mutation of IKKβ in mouse embryonic fibroblast cells indicating involvement of the NF-κB pathway. Serum-induced SGK or increased expression of SGK activated NF-κB transcriptional activity, whereas small interference RNA to SGK blocked NF-κB activity. Coexpression of SGK and IKKβ significantly increased the activation of NF-κB (versus expression of IKKβ alone). Expression of dominant-negative IKKβ K44A, IκBα AA, and kinase-dead SGK (127KM) blocked the ability of SGK to stimulate NF-κB activity, suggesting that IKKβ is a target of SGK. We also show that SGK enhances the ability of IKKβ to phosphorylate endogenous IκBα in cells or recombinant glutathione S-transferase-IκBα in vitro and increases IκBα degradation; SGK physically associates with and activates IKKβ in MDA231 cells via phosphorylation of Ser181 in IKKβ. Taken together, we conclude that SGK acts as an oncogene in breast cancer cells through activation of the IKK-NF-κB pathway, thereby preventing apoptosis. Blocking SGK expression/activity represents a potential therapeutic approach for breast cancer treatment.