Inhibition of STAT3 Signaling Blocks the Anti-apoptotic Activity of IL-6 in Human Liver Cancer Cells

Department of Pediatrics, Center for Childhood Cancer, The Research Institute at Nationwide Children's Hospital, The Ohio State University, Columbus, Ohio 43205, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 08/2010; 285(35):27429-39. DOI: 10.1074/jbc.M110.142752
Source: PubMed


Interleukin-6 (IL-6) is a multifunctional cytokine, which may block apoptosis during inflammation to protect cells under very toxic conditions. However, IL-6 also activates STAT3 in many types of human cancer. Recent studies demonstrate that high levels of IL-6 are associated with hepatocellular carcinoma, the most common type of liver cancer. Here we reported that IL-6 promoted survival of human liver cancer cells through activating STAT3 in response to doxorubicin treatment. Endogenous IL-6 levels in SNU-449 cells were higher than in Hep3B cells. Meanwhile, SNU-449 cells were more resistant to doxorubicin than Hep3B cells. Addition of IL-6 induced STAT3 activation in Hep3B cells and led to protection against doxorubicin. In contrast, neutralizing IL-6 with anti-IL-6 antibody decreased survival of SNU-449 cells in response to doxorubicin. To elucidate the mechanism of the anti-apoptotic function of IL-6, we investigated if STAT3 mediated this drug resistance. Targeting STAT3 with STAT3 siRNA reduced the protection of IL-6 against doxorubicin-induced apoptosis, indicating that STAT3 signaling contributed to the anti-apoptotic effect of IL-6. Moreover, we further explored if a STAT3 small molecule inhibitor could abolish this anti-apoptotic effect. LLL12, a STAT3 small molecule inhibitor, blocked IL-6-induced STAT3 phosphorylation, resulting in attenuation of the anti-apoptotic activity of IL-6. Finally, neutralization of endogenous IL-6 with anti-IL-6 antibody or blockade of STAT3 with LLL12 lowered the recovery in SNU-449 cells after doxorubicin treatment. Therefore, our results demonstrated that targeting STAT3 signaling could interrupt the anti-apoptotic function of IL-6 in human liver cancer cells.

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    • "Acquiring resistance to apoptosis appears an important feature for the development of hormone resistant and aggressive human prostate cancer. Furthermore, IL6 was shown to act as a survival factor, blocking apoptosis induced by Bcl-xl, p53, TGF1β [137], and cytotoxic agents such as doxorubicin [138] and enzalutamide [139]. Whereas siRNA or STAT3-inhibitor-AG490 mediated suppression of the downstream acting STAT diminished the IL6 induced antiapoptotic function [138, 139]. "
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    ABSTRACT: Prostate cancer is worldwide the sixth leading cause of cancer related death in men thus early detection and successful treatment are still of major interest. The commonly performed screening of the prostate-specific antigen (PSA) is controversially discussed, as in many patients the prostate-specific antigen levels are chronically elevated in the absence of cancer. Due to the unsatisfying efficiency of available prostate cancer screening markers and the current treatment outcome of the aggressive hormone refractory prostate cancer, the evaluation of novel molecular markers and targets is considered an issue of high importance. MicroRNAs are relatively stable in body fluids orchestrating simultaneously the expression of many genes. These molecules are currently discussed to bear a greater diagnostic potential than protein-coding genes, being additionally promising therapeutic drugs and/or targets. Herein we review the potential impact of the microRNA let-7 family on prostate cancer and show how deregulation of several of its target genes could influence the cellular equilibrium in the prostate gland, promoting cancer development as they do in a variety of other human malignant neoplasias.
    BioMed Research International 09/2014; 2014:376326. DOI:10.1155/2014/376326 · 2.71 Impact Factor
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    • "Twenty-two genes were differentially regulated by atrogin-1 overexpression (Table 1). Eight of them including Csf2 [23]–[25], IL-6 [26]–[28] and Aldh1a3 [29] were down-regulated, which were involved in negative regulation of apoptosis. Conversely, fourteen of them including Msx2 [30] and Axin2 [31] were up-regulated, which mediated positive regulation of apoptosis. "
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    PLoS ONE 07/2013; 8(1):e53831. DOI:10.1371/journal.pone.0053831 · 3.23 Impact Factor
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    • "Further, evidence showed that DAPs activates cleaved caspase-3 and induces apoptotic markers of PARP in various cancer cell lines, suggesting that DAPs induce apoptosis in cancer cells by targeting STAT3 proteins [64]. Many reports have shown that blockage of constitutive STAT3 activation and signaling results in growth inhibition and induction of apoptosis in tumor cells both in vitro and in vivo[131-133]. However, DAP-F(p)-NOH may also inhibit STAT3 activation through JAK2, Src, Erb2, and epidermal growth factor receptor (EGFR), which are implicated in STAT3 activation as well. "
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