Stress Hormones Regulate Interleukin-6 Expression by Human Ovarian Carcinoma Cells through a Src-dependent Mechanism

Department of Psychology, University of Iowa, Iowa City, Iowa, United States
Journal of Biological Chemistry (Impact Factor: 4.57). 11/2007; 282(41):29919-26. DOI: 10.1074/jbc.M611539200
Source: PubMed


Recent studies have demonstrated that chronic stress promotes tumor growth, angiogenesis, and metastasis. In ovarian cancer, levels of the pro-angiogenic cytokine, interleukin 6 (IL-6), are known to be elevated in individuals experiencing chronic stress, but the mechanism(s) by which this cytokine is regulated and its role in tumor growth remain under investigation. Here we show that stress hormones such as norepinephrine lead to increased expression of IL-6 mRNA and protein levels in ovarian carcinoma cells. Furthermore, we demonstrate that norepinephrine stimulation activates Src tyrosine kinase and this activation is required for increased IL-6 expression. These results demonstrate that stress hormones activate signaling pathways known to be critical in ovarian tumor progression.

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    • "Maximum elevations in IL-6 occurred at an early time (1 h), giving evidence of fast metabolism of adrenergic mediators by OSCC cells. Nilsson et al. (2007) found that maximum increases in IL-6 expression in ovarian carcinoma cells occurred only after 6 h of incubation with NE. Nilsson's results after 3 h of treatment of these same cells with NE showed just a minimum rise in IL-6 production. "
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    ABSTRACT: Patients with oral cancer can have high psychological distress levels, but the effects of stress-related hormones on oral cancer cells and possible mechanisms underlying these relationships are unknown. In this study, we have investigated the effects of stress-related hormones on interleukin-6 (IL-6) secretion and proliferation of oral squamous cell carcinoma (OSCC) cells. The effects of norepinephrine (NE), and cortisol were studied in SCC9, SCC15, and SCC25 cells and effects of isoproterenol in SCC9 and SCC25 cells. Real-time PCR studies revealed constitutive b1- and b2-adrenergic receptors (b-ARs) expression in the SCC9, SCC15, and SCC25 cells. The results showed that NE and isoproterenol significantly enhanced IL-6 mRNA expression and protein production in supernatants of SCC9 and SCC25 cells. Physiological stress levels of NE and isoproterenol (10 lM) at 1 h elicited the most robust IL-6 increase. Regarding IL-6 secretion, 10 lM NE induced a 5-fold increase at 1 h, 3.7-fold increase at 6 h, and 3.2-fold at 24 h in SCC9 cells. These effects were blocked by the b-adrenergic antagonist propranolol, supporting a role for b-ARs in IL-6 secretion. The effects of cortisol varied according to the hormone concentration. Pharmacological concentrations of cortisol (1000 nM) inhibited IL-6 production by SCC9 and SCC25 cells. Cortisol dose that simulates stress conditions (10 nM) tended to increase IL-6 expression in SCC9 cells. Hormonal doses that simulate stress conditions (10 lM NE, at 6 h in SCC9 and SCC15 cells and 10 nM cortisol, at 48 h in SCC15 cells) stimulated increased cell proliferation. Treatment of SCC9 cells with IL-6 neutralizing ab (10 lg/mL) partially inhibited NE-induced proliferation. Finally, 20 OSCC biopsies were shown to express b1- and b2-ARs. These findings suggest that stress hormones can affect oral cancer cells behavior.
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    • "Similarly, AP-1 activation via PKA and p38 MAPK (p38 mitogen-activated protein kinase) is reported to contribute to IL-6 induction in osteoblastic cells under β-adrenergic stimulation (34). In contrast, it has been demonstrated that only the C/EBP-β (NF-IL-6) motif is involved in NE-mediated IL-6 expression (7) in human ovarian carcinoma cells. Although the NF-κB binding site is reported to be involved in many stimuli (28,35,36), it is not essential for NE-mediated IL-6 expression in GES-1 cells. "
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    ABSTRACT: In the current literature, there is evidence that psychological factors can affect the incidence and progression of some cancers. Interleukin 6 (IL-6) is known to be elevated in individuals experiencing chronic stress and is also involved in oncogenesis and cancer progression. However, the precise mechanism of IL-6 induction by the stress-related hormone norepinephrine (NE) is not clear, and, furthermore, there are no reports about the effect of NE on IL-6 expression in gastric epithelial cells. In this study, we examined the effect of NE on IL-6 expression in immortalized human gastric epithelial cells (GES-1 cells). Using real-time PCR and enzyme-linked immunoassay, we demonstrated that NE can induce IL-6 mRNA and protein expression in GES-1 cells. The induction is through the β-adrenergic receptor-cAMP-protein kinase A pathway and mainly at the transcriptional level. Progressive 5'-deletions and site-directed mutagenesis of the parental construct show that, although activating-protein-1 (AP-1), cAMP-responsive element binding protein (CREB), CCAAT-enhancer binding protein-β (C/EBP-β), and nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) binding sites are all required in the basal transcription of IL-6, only AP-1 and CREB binding sites in the IL-6 promoter are required in NE-induced IL-6 expression. The results suggest that chronic stress may increase IL-6 secretion of human gastric epithelial cells, at least in part, by the stress-associated hormone norepinephrine, and provides basic data on stress and gastric cancer progression.
    Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas / Sociedade Brasileira de Biofisica ... [et al.] 02/2014; 47(2):101-9. DOI:10.1590/1414-431X20133346 · 1.01 Impact Factor
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    • "Although Il6 mRNA levels did not change with obesity in peri-ovarian adipose tissue, there were elevated Il6 mRNA levels in the ovaries of obese mice compared to lean mice. Elevated levels of IL6 have been reported in patients with ovarian hyperstimulation syndrome (Buyalos et al., 1992; Loret de Mola et al., 1996a; Loret de Mola et al., 1996b), epithelial ovarian cancer (Lane et al., 2011), as well as other forms of ovarian cancer (Costanzo et al., 2005; Nilsson et al., 2007). IL6, together with TNFa and IL1b, has also been reported to be part of the cytokine network implicated in ovarian cancer (Anglesio et al., 2011; Coward et al., 2011; Kulbe et al., 2007). "
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    ABSTRACT: Dysregulation of immune cells and/or altered inflammatory signaling have been implicated with reproductive dysfunction. Physiological changes leading to perturbations in the profile of immune cells and/or pro-inflammatory cytokines in or around female reproductive tissue could potentially have profound effects on ovarian function. Obesity is associated with chronic low-grade inflammation due, in part, to increased immune cell infiltration and inflammation in visceral adipose depots. This study investigated the impact of diet-induced obesity on immune cell infiltration and inflammation in peri-ovarian adipose tissue and mRNA expression of key inflammatory markers and microRNAs (miRs) in ovarian tissue. Six-week-old female C57Bl/6J mice were fed a standard chow or high-fat diet (HFD; 60% kcal fat) for approximately 7 months, at which time peri-ovarian adipose tissue and ovarian tissues were collected. Histological analysis of peri-ovarian adipose tissue from obese mice revealed increased (P < 0.05) adipocyte size and the presence of crown-like structures, the morphological presentation of infiltrating immune cells in adipose tissue, along with increases (P < 0.05) in the mRNA levels of markers of T-cells, activated macrophages, inflammatory cytokines, and chemokines. Ovarian mRNA levels of Il1b, Il6, Tnfa, p55, p75, Ccl2, Ikbkb, and Rela were higher in obese tissue (P < 0.05), with a strong trend (P = 0.06) for an increase in Nos2 and RELA protein. Additionally, ovarian miR125b and miR143 levels were decreased (P = 0.1). These data demonstrate that diet-induced obesity elevates expression of inflammatory-mediator genes in both the ovary and surrounding adipose depot, potentially negatively affecting ovarian function. Mol. Reprod. Dev. © 2013 Wiley Periodicals, Inc.
    Molecular Reproduction and Development 11/2013; 80(11). DOI:10.1002/mrd.22231 · 2.53 Impact Factor
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