Luteolin sensitizes the antiproliferative effect of interferon ?/? 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.
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-?/?) 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-? in hepatoma HepG2 cells and cervical carcinoma HeLa cells. Luteolin promoted IFN-?-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-?-regulated gene expression. Of interest, inhibition of phosphodiesterase (PDE) abolished the effect of IFN-? 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-?-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-?/?.
Mesh Terms:
Adjuvants, Immunologic, Antibodies, Cell Line, Tumor, Cell Proliferation, Cell Survival, Colforsin, Cyclic AMP, Cyclic AMP-Dependent Protein Kinases, GTP-Binding Proteins, HEK293 Cells, HeLa Cells, Hep G2 Cells, Humans, Immunologic Factors, Interferon-alpha, Interferon-beta, Janus Kinase 1, Luteolin, Neoplasm Proteins, Phosphodiesterase Inhibitors, Phosphoric Diester Hydrolases, Phosphorylation, Protein Tyrosine Phosphatase, Non-Receptor Type 11, Receptor, Interferon alpha-beta, Receptors for Activated C Kinase, Receptors, Cell Surface, STAT1 Transcription Factor, STAT2 Transcription Factor, Signal Transduction, TYK2 Kinase
Adjuvants, Immunologic, Antibodies, Cell Line, Tumor, Cell Proliferation, Cell Survival, Colforsin, Cyclic AMP, Cyclic AMP-Dependent Protein Kinases, GTP-Binding Proteins, HEK293 Cells, HeLa Cells, Hep G2 Cells, Humans, Immunologic Factors, Interferon-alpha, Interferon-beta, Janus Kinase 1, Luteolin, Neoplasm Proteins, Phosphodiesterase Inhibitors, Phosphoric Diester Hydrolases, Phosphorylation, Protein Tyrosine Phosphatase, Non-Receptor Type 11, Receptor, Interferon alpha-beta, Receptors for Activated C Kinase, Receptors, Cell Surface, STAT1 Transcription Factor, STAT2 Transcription Factor, Signal Transduction, TYK2 Kinase
Cell Signal
Date: Mar. 01, 2014
PubMed ID: 24333668
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