Luteolin sensitizes the antiproliferative effect of interferon 伪/尾 by activation of Janus kinase/signal transducer and activator of transcription pathway signaling through protein kinase A-mediated inhibition of protein tyrosine phosphatase SHP-2 in cancer cells

详细信息    查看全文

• 作者：Zhengfu Tai ; Yuan Lin ; Yujiao He ; Junmei Huang ; Jiajia Guo ; Lijuan Yang ; Guolin Zhang ; Fei Wang
• 关键词：luteolin ; 3&prime ; 4&prime ; 5 ; 7-tetrahydroxyflavone ; IFN ; interferon ; JAK ; Janus kinase ; STAT ; signal transducer and activator of transcription ; ISRE ; interferon 伪-stimulated response element ; PDE ; phosphodiesterase ; cAMP ; cyclic adenosine 3&prime ; 5&prime ; -monophosphate ; IFNAR ; type I interferon receptor ; PKA ; cAMP-dependent protein kinase A ; SHP ; Src homology domain 2 containing phosphotyrosine phosphatase ; PKC ; protein kinase C ; AKAP ; A-kinase anchoring protein ; RACK-1 ; receptor for activate
• 刊名：Cellular Signalling
• 出版年：March, 2014
• 年：2014
• 卷：26
• 期：3
• 页码：619-628
• 全文大小：1053 K

文摘

New negative regulators of interferon (IFN) signaling, preferably with tissue specificity, are needed to develop therapeutic means to enhance the efficacy of type I IFNs (IFN-伪/尾) and reduce their side effects. We conducted cell-based screening for IFN signaling enhancer and discovered that luteolin, a natural flavonoid, sensitized the antiproliferative effect of IFN-伪 in hepatoma HepG2 cells and cervical carcinoma HeLa cells. Luteolin promoted IFN-尾-induced Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway activation by enhancing the phosphorylation of Jak1, Tyk2, and STAT1/2, thereby promoting STAT1 accumulation in the nucleus and endogenous IFN-伪-regulated gene expression. Of interest, inhibition of phosphodiesterase (PDE) abolished the effect of IFN-尾 and luteolin on STAT1 phosphorylation. Luteolin also increased the cAMP-degrading activity of PDE bound with type I interferon receptor 2 (IFNAR2) and decreased the intracellular cAMP level, indicating that luteolin may act on the JAK/STAT pathway via PDE. Protein kinase A (PKA) was found to negatively regulate IFN-尾-induced JAK/STAT signaling, and its inhibitory effect was counteracted by luteolin. Pull-down and immunoprecipitation assays revealed that type II PKA interacted with IFNAR2 via the receptor for activated C-kinase 1 (RACK-1), and such interaction was inhibited by luteolin. Src homology domain 2 containing tyrosine phosphatase-2 (SHP-2) was further found to mediate the inhibitory effect of PKA on the JAK/STAT pathway. These data suggest that PKA/PDE-mediated cAMP signaling, integrated by RACK-1 to IFNAR2, may negatively regulate IFN signaling through SHP-2. Inhibition of this signaling may provide a new way to sensitize the efficacy of IFN-伪/尾.