IL-6 activates serum and glucocorticoid kinase via p38α mitogen-activated protein kinase pathway

Interleukin-6 (IL-6) has been implicated as an autocrine factor involved in growth of several human cancers, such as tumors arising from the biliary tract or cholangiocarcinoma. In malignant biliary tract epithelia, IL-6 activates the p38 MAPK pathway, which mediates a dominant survival signaling pa...

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Autors principals: Meng, Fanyin, Yamagiwa, Yoko, Taffetani, Silvia, Han, Jiahuai, Patel, Tushar
Format: Article
Idioma:English
Publicat: 2005
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Article
Accés en línia:https://ncbi.nlm.nih.gov/pmc/articles/PMC1513290/
https://ncbi.nlm.nih.gov/pubmed/15917303
https://ncbi.nlm.nih.govhttp://dx.doi.org/10.1152/ajpcell.00081.2005
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Sumari:Interleukin-6 (IL-6) has been implicated as an autocrine factor involved in growth of several human cancers, such as tumors arising from the biliary tract or cholangiocarcinoma. In malignant biliary tract epithelia, IL-6 activates the p38 MAPK pathway, which mediates a dominant survival signaling pathway. Serum and glucocorticoid-stimulated kinase (SGK) has been implicated as a survival kinase, but its role in survival signaling by IL-6 is unknown. After IL-6 stimulation, p38 MAPK activation preceded phosphorylation of SGK at Ser(78). Pretreatment with the pharmacological inhibitors of p38 MAPK SB-203580 or SB-202190 blocked IL-6-induced SGK phosphorylation at Ser(78) and SGK activation. Overexpression of p38α increased constitutive SGK phosphorylation at Ser(78), whereas dominant negative p38α MAPK blocked IL-6-induced SGK phosphorylation and nuclear translocation. Interestingly, in addition to stimulating SGK phosphorylation, both IL-6 stimulation and p38α MAPK overexpression increased SGK mRNA and protein expression. An increase in p38 MAPK and SGK occurred following enforced expression of IL-6 in vivo. Furthermore, inhibition of SGK expression by siRNA increased toxicity due to chemotherapeutic drugs. Taken together, these data identify SGK as both a downstream kinase substrate as well as a transcriptionally regulated gene target of p38 MAPK in response to IL-6 and support a role of SGK during survival signaling by IL-6 in human cancers, such as cholangiocarcinoma.

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