STATs in cancer inflammation and immunity: A leading role for STAT3

Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California 91010, USA.
Nature Reviews Cancer (Impact Factor: 29.54). 11/2009; 9(11):798-809. DOI: 10.1038/nrc2734
Source: PubMed

ABSTRACT Commensurate with their roles in regulating cytokine-dependent inflammation and immunity, signal transducer and activator of transcription (STAT) proteins are central in determining whether immune responses in the tumour microenvironment promote or inhibit cancer. Persistently activated STAT3 and, to some extent, STAT5 increase tumour cell proliferation, survival and invasion while suppressing anti-tumour immunity. The persistent activation of STAT3 also mediates tumour-promoting inflammation. STAT3 has this dual role in tumour inflammation and immunity by promoting pro-oncogenic inflammatory pathways, including nuclear factor-kappaB (NF-kappaB) and interleukin-6 (IL-6)-GP130-Janus kinase (JAK) pathways, and by opposing STAT1- and NF-kappaB-mediated T helper 1 anti-tumour immune responses. Consequently, STAT3 is a promising target to redirect inflammation for cancer therapy.

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Available from: Hua Yu, May 15, 2014
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    • "Please cite this article in press as: Alexandros G. Georgakilas, et al., Emerging molecular networks common in ionizing radiation, immune and inflammatory responses by employing bioinformatics approaches, Cancer Letters (2015), doi: 10.1016/j.canlet.2015.03.021 has been shown to have minimum expression changes in the case of low-LET X-rays [26] but a significant increase in the case again of space high-LET radiation [74]. Other interactions of the NFKB family are but not limited to: CD14 and TLR2 which are shown to mediate innate immunity and inflammation [75], the cytokine IL1 receptor 2 (IL1R2) which is implicated in immune regulation [76], FOS having a pivotal role in osteoimmunity [77], STAT3 which is shown to have a key function in inflammation and immune response [78], JAK2 which participates in innate immune response [79] [80] and ICAM1 playing a leading role in the immune cell–cell interactions [81]. The NFKB inhibitors, NFKBIA and NFKBIE [72], as expected, appear to inhibit NFKB1, NFKB2 and RELA (Fig. 2). "
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    ABSTRACT: Efficient radiation therapy is characterized by enhanced tumor cell killing involving the activation of the immune system (tumor immunogenicity) but at the same time minimizing chronic inflammation and radiation adverse effects in healthy tissue. The aim of this study was to identify gene products involved in immune and inflammatory responses upon exposure to ionizing radiation by using various bioinformatic tools. Ionizing radiation is known to elicit different effects at the level of cells and organism i.e. DNA Damage Response (DDR), DNA repair, apoptosis and, most importantly, systemic effects through the instigation of inflammatory 'danger' signals and innate immune response activation. Genes implicated both in radiation and immune/inflammatory responses were collected manually from the scientific literature with a combination of relevant keywords. The experimentally validated and literature-based results were inspected, and genes involved in radiation, immune and inflammatory response were pooled. This kind of analysis was performed for the first time, for both healthy and tumor tissues. In this way, a set of 24 genes common in all three different phenomena was identified. These genes were found to form a highly connected network. Useful conclusions are drawn regarding the potential application of these genes as markers of response to radiation for both healthy and tumor tissues through the modulation of immune and/or inflammatory mechanisms. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
    Cancer letters 04/2015; DOI:10.1016/j.canlet.2015.03.021 · 5.02 Impact Factor
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    • "STAT3, STAT4, STAT5 and STAT6 play a critical role in the complex diseases like cancer and diabetes and are believed to possess pro-proliferative and antiinflammatory associated activities which are thought to be crucial for successful regulation of proliferation and differentiation of the cells (Friedbichler et al., 2009; Gooch et al., 2002; Grivennikov and Karin, 2010; Schindler et al., 2007; Takeda et al., 1997). However, aberrant signaling by STAT3 has been reported in a variety of malignancies, including the breast and prostate cancer (Aggarwal et al., 2009; Azare et al., 2007; Huang et al., 2005b; Yue and Turkson, 2009). Consequently, it is reported that overactivated STAT3 and STAT5 increase tumor cell proliferation and invasion while suppressing anti-tumor immunity (Yu et al., 2007, 2009). "
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    ABSTRACT: Signal transducer and activator of transcription (STAT) family, encompassing protein molecules that function as a second messenger and transcription factor, are famously known to regulate a multitude of cellular processes including inflammation, cell proliferation, invasion, angiogenesis, metastasis and immune system homeostasis. STAT3 is one of the six members of a family of transcription factors. STAT3 has proved themselves to be interesting candidates for anticancer therapy as they are over-expressed in most cancer cells. Thus, we studied receptor-based molecular docking of STAT3 against natural compounds and further validations of lead molecules in an array of cancer cells. In the present study, we screened approximately 50,000 natural compounds from the IBS. All natural compounds were docked with the X-ray crystal structure of STAT3 (PDB; 1BG1) retrieved from the protein data bank by using Maestro 9.6 (Schrödinger Inc). First, we performed high-throughput virtual screening of IBS against the SH2 domain of STAT3. Further, best 20 compounds that possess minimal Gscore along with 85 natural compounds that had been reported in published literature as having anticancer properties were selected, and molecular docking was performed using the XP (extra precision) mode of GLIDE. We analyzed Gscore and protein–ligand interactions of top ranking compounds. It was discovered in this study, compounds CID252682, CID5281670 (Morin), CID5281672 (Myricetin), CID72277 (Epigallocatechol) and CID65064 (Epigallocatechin Gallate, EGCG) yielded the excellent dock score with the STAT3 concluded with the help of docking-free energy. Moreover, IBS STOCK1N-43090, STOCK1N-66505, STOCK1N-54303, STOCK1N-44634, STOCK1N-45027, STOCK1N-73784, STOCK1N-69597, STOCK1N-73062, STOCK1N-81915 and STOCK1N-70844 have better docking-free energy. Further, we chose EGCG and myricetin compounds, and their effect on biological activity such as cell proliferation, oxidative stress, colony formation, mRNA expression of STAT3, and cell number was reported after the 48 h treatments in cancer cell lines. EGCG and myricetin reduce the STAT3 mRNA expression confirmed by RTPCR. Moreover, EGCG and myricetin reduce cell proliferation and ROS generation after 48 h treatments. Interestingly, our result also indicates that the reduction in potential for colony formation enhances anti-metastasis activity of EGCG and myricetin. The information obtained from our study assisted us in drawing a more lucid picture regarding the existence STAT3 natural compounds inhibitor on diverse cancer cells.
    Medicinal Chemistry Research 02/2015; 24(6). DOI:10.1007/s00044-015-1328-6 · 1.61 Impact Factor
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    • "These results increase a possibility that ANE enhances inflammation in oral mucosa at least via facilitating dephosphorylation of nuclear STAT3. Activated STAT3 is associated with inflammation during tumor progress [26]. However, ANE may modulate the transcription of a few inflammatory cytokines by enhancing Y705 dephosphorylation of STAT3 since un-and phosphorylated STAT3 had been reported to differently regulate several downstream targets [27] "
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    ABSTRACT: Betel quid chewing is associated with various pathologic alterations in oral mucosa. However, the molecular mechanism behind so many contradictory alterations remains unclear. Here we aimed to build a model to facilitate the related studies in cultured cells. In our results, areca nut extract (ANE) was found to exert different effects in oral cells depending on the supplemented serum level. ANE strongly induced DNA damage, necrotic ballooning, and inflammatory cytokines under lower serum concentration while might convert to facilitate deregulated growth of serum-supplemented cells via modulating the activity/expression of factors such as E-cadherin and Snail. Despite ANE significantly activated NF-κB, a mediator critical for inflammation, inhibition of NF-κB did not prevent the activation of IL8 promoter. We further discovered Y705-dephosphorylated STAT3 might enhance IL8 transcription. Since necrosis and the inflammatory cytokines could cause massive inflammation, infiltration of interstitial fluid might potentiate cellular resistance against the acute cytotoxicity of ANE and further support the proliferation of transforming cells. Induction of VEGF and angiogenesis under lower serum condition also paved the way for cell growth and subsequent metastasis. Accordingly, we concluded that in correlation with serum infiltration ANE caused particular effects in oral cells and possibly the various clinicopathological alterations in vivo.
    Toxicology Reports 11/2014; 1. DOI:10.1016/j.toxrep.2014.10.018
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