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Dietary quercetin potentiates the antiproliferative effect of interferon-? in hepatocellular carcinoma cells through activation of JAK/STAT pathway signaling by inhibition of SHP2 phosphatase.

ABSTRACT: Type I interferons (IFN-?/?) have broad and potent immunoregulatory and antiproliferative activities, which are negatively regulated by Src homology domain 2 containing tyrosine phosphatase-2 (SHP-2). Inhibition of SHP2 by small molecules may be a new strategy to enhance the effcacy of type I IFNs. Using an in vitro screening assay for new inhibitors of SHP2 phosphatase, we found that quercetin was a potent inhibitor of SHP2. Computational modeling showed that quercetin exhibited an orientation favorable to nucleophilic attack in the phosphatase domain of SHP2. Quercetin enhanced the phosphorylation of signal transducer and activator of transcription proteins 1 (STAT1) and promoted endogenous IFN-?-regulated gene expression. Furthermore, quercetin also sensitized the antiproliferative effect of IFN-? on hepatocellular carcinoma HepG2 and Huh7 cells. The overexpression of SHP2 attenuated the effect of quercetin on IFN-?-stimulated STAT1 phosphorylation and antiproliferative effect, whereas the inhibition of SHP2 promoted the effect of quercetin on IFN-?-induced STAT1 phosphorylation and antiproliferative effect. The results suggested that quercetin potentiated the inhibitory effect of IFN-? on cancer cell proliferation through activation of JAK/STAT pathway signaling by inhibiting SHP2. Quercetin warrants further investigation as a novel therapeutic method to enhance the efficacy of IFN-?/?.

SUBMITTER: Igbe I

PROVIDER: S-EPMC5768359 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Project description:BackgroundCell-to-cell heterogeneity is an inherent feature of multicellular organisms and is central in all physiological and pathophysiological processes including cellular signal transduction. The cytokine IL-6 is an essential mediator of pro- and anti-inflammatory processes. Dysregulated IL-6-induced intracellular JAK/STAT signalling is associated with severe inflammatory and proliferative diseases. Under physiological conditions JAK/STAT signalling is rigorously controlled and timely orchestrated by regulatory mechanisms such as expression of the feedback-inhibitor SOCS3 and activation of the protein-tyrosine phosphatase SHP2 (PTPN11). Interestingly, the function of negative regulators seems not to be restricted to controlling the strength and timely orchestration of IL-6-induced STAT3 activation. Exemplarily, SOCS3 increases robustness of late IL-6-induced STAT3 activation against heterogenous STAT3 expression and reduces the amount of information transferred through JAK/STAT signalling.MethodsHere we use multiplexed single-cell analyses and information theoretic approaches to clarify whether also SHP2 contributes to robustness of STAT3 activation and whether SHP2 affects the amount of information transferred through IL-6-induced JAK/STAT signalling.ResultsSHP2 increases robustness of both basal, cytokine-independent STAT3 activation and early IL-6-induced STAT3 activation against differential STAT3 expression. However, SHP2 does not affect robustness of late IL-6-induced STAT3 activation. In contrast to SOCS3, SHP2 increases the amount of information transferred through IL-6-induced JAK/STAT signalling, probably by reducing cytokine-independent STAT3 activation and thereby increasing sensitivity of the cells. These effects are independent of SHP2-dependent MAPK activation.ConclusionIn summary, the results of this study extend our knowledge of the functions of SHP2 in IL-6-induced JAK/STAT signalling. SHP2 is not only a repressor of basal and cytokine-induced STAT3 activity, but also ensures robustness and transmission of information. Plain English summary Cells within a multicellular organism communicate with each other to exchange information about the environment. Communication between cells is facilitated by soluble molecules that transmit information from one cell to the other. Cytokines such as interleukin-6 are important soluble mediators that are secreted when an organism is faced with infections or inflammation. Secreted cytokines bind to receptors within the membrane of their target cells. This binding induces activation of an intracellular cascade of reactions called signal transduction, which leads to cellular responses. An important example of intracellular signal transduction is JAK/STAT signalling. In healthy organisms signalling is controlled and timed by regulatory mechanisms, whose activation results in a controlled shutdown of signalling pathways. Interestingly, not all cells within an organism are identical. They differ in the amount of proteins involved in signal transduction, such as STAT3. These differences shape cellular communication and responses to intracellular signalling. Here, we show that an important negative regulatory protein called SHP2 (or PTPN11) is not only responsible for shutting down signalling, but also for steering signalling in heterogeneous cell populations. SHP2 increases robustness of STAT3 activation against variable STAT3 amounts in individual cells. Additionally, it increases the amount of information transferred through JAK/STAT signalling by increasing the dynamic range of pathway activation in heterogeneous cell populations. This is an amazing new function of negative regulatory proteins that contributes to communication in heterogeneous multicellular organisms in health and disease. Video Abstract.

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Dietary quercetin potentiates the antiproliferative effect of interferon-? in hepatocellular carcinoma cells through activation of JAK/STAT pathway signaling by inhibition of SHP2 phosphatase.

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