Antiapoptotic effect of serum and glucocorticoid-inducible protein kinase is mediated by novel mechanism activating I{kappa}B kinase.

Antiapoptotic effect of serum and glucocorticoid-inducible protein kinase is mediated by novel mechanism activating I{kappa}B kinase.
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DOI：
10.1158/0008-5472.457.65.2
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发表时间：
2005-01
期刊：
Cancer research
影响因子：
11.2
通讯作者：
Liping Zhang;Ruwen Cui;Xiaodong Cheng;Jie Du
Liping Zhang;Ruwen Cui;Xiaodong Cheng;Jie Du
中科院分区：
医学1区
文献类型：
--
作者：
Liping Zhang;Ruwen Cui;Xiaodong Cheng;Jie Du

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血清和糖皮质激素诱导的蛋白激酶（SGK）在促进细胞存活中起着至关重要的作用，但这种反应的机制尚不清楚。我们发现，SGK是通过调节核转录因子κ B（NF-κ B）的转录活性参与乳腺癌细胞凋亡的调节。在人乳腺癌样品中观察到高水平的SGK表达。当SGK降低时，凋亡率增加，并且增加的SGK活性防止血清撤回诱导的凋亡。SGK诱导的细胞存活被IkappaB激酶β（IKK β，K44 A）的显性阴性形式或小鼠胚胎成纤维细胞中IKK β的无效突变所消除，表明NF-κ B通路的参与。血清诱导的SGK或SGK表达增加激活NF-κ B转录活性，而SGK的小干扰RNA阻断NF-κ B活性。SGK和IKK β的共表达显著增加了NF-κ B的活化（相对于IKK β单独表达）。显性阴性IKK β K44 A、IKK β AA和激酶死亡的SGK（127 KM）的表达阻断了SGK刺激NF-κ B活性的能力，表明IKK β是SGK的靶点。我们还发现，SGK增强IKK β磷酸化细胞内内源性IkappaB α或重组谷胱甘肽S-转移酶-IkappaB α的能力，并增加IkappaB α的降解; SGK通过IKK β中Ser（181）的磷酸化与MDA 231细胞中的IKK β物理结合并激活IKK β。综上所述，我们得出结论，SGK作为一种癌基因在乳腺癌细胞中通过激活IKK-NF-kappaB通路，从而防止细胞凋亡。阻断SGK表达/活性代表了乳腺癌治疗的潜在治疗方法。
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 kappaB (NF-kappaB). 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 IkappaB kinase beta (IKKbeta, K44A) or a null mutation of IKKbeta in mouse embryonic fibroblast cells indicating involvement of the NF-kappaB pathway. Serum-induced SGK or increased expression of SGK activated NF-kappaB transcriptional activity, whereas small interference RNA to SGK blocked NF-kappaB activity. Coexpression of SGK and IKKbeta significantly increased the activation of NF-kappaB (versus expression of IKKbeta alone). Expression of dominant-negative IKKbeta K44A, IkappaBalpha AA, and kinase-dead SGK (127KM) blocked the ability of SGK to stimulate NF-kappaB activity, suggesting that IKKbeta is a target of SGK. We also show that SGK enhances the ability of IKKbeta to phosphorylate endogenous IkappaBalpha in cells or recombinant glutathione S-transferase-IkappaBalpha in vitro and increases IkappaBalpha degradation; SGK physically associates with and activates IKKbeta in MDA231 cells via phosphorylation of Ser(181) in IKKbeta. Taken together, we conclude that SGK acts as an oncogene in breast cancer cells through activation of the IKK-NF-kappaB pathway, thereby preventing apoptosis. Blocking SGK expression/activity represents a potential therapeutic approach for breast cancer treatment.