UNIPROT:P05231 - FACTA Search

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Query: UNIPROT:P05231 (interleukin-6)
23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interleukin-6 (IL-6) is a multifunctional cytokine which is involved in regulation of growth of various malignant tumors. IL-6 binds to its receptor, which is composed of a ligand-binding and a signal-transducing subunit and activates pathways of signal transducers and activators of transcription and mitogen-activated protein kinases (MAPKs). In prostate cancer cells, IL-6 induces divergent proliferative responses. Serum levels of IL-6 are elevated in patients with therapy-resistant carcinoma of the prostate. We have investigated whether IL-6 interacts with the androgen signaling pathway in prostate cancer cells. In DU-145 cells, transiently transfected with androgen receptor (AR) cDNA, IL-6 caused ligand-independent and synergistic activation of the AR. Nonsteroidal antagonists of the AR down-regulated AR activity induced by IL-6. In LNCaP cells, IL-6-induced expression of the AR-regulated prostate-specific antigen gene. Inhibitors of protein kinase A and C and MAPK down-regulated IL-6-induced AR activity. IL-6 expression in human prostate tissue was studied by immunohistochemistry. In benign prostatic tissue, IL-6 immunoreactivity was confined to basal cells. In prostate intraepithelial neoplasia and in cancer tissue, atypical intraluminal and cancer cells expressed IL-6. The expression of IL-6 receptor was demonstrated in benign and malignant tissue in both epithelium and stroma. In the authors' laboratory, IL-6-inhibited proliferation of parental LNCaP cells. A new LNCaP subline was generated to investigate changes in signal transduction which might occur after prolonged treatment with IL-6. In the subline LNCaP-IL-6+, IL-6 neither reduced a number of cells nor caused G1 growth arrest. IL-6 receptor expression declined during long-term IL-6 treatment. However, IL-6-up-regulated AR expression and was capable of inducing AR activity in LNCaP-IL-6+ cells. Parental LNCaP cells do not express IL-6. In contrast, IL-6 mRNA and protein expression were detectable in high passages of LNCaP-IL-6+ cells. Thus changes in signal transduction occur in prostate cancer cells after prolonged IL-6 treatment
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PMID:Interleukin-6 regulates androgen receptor activity and prostate cancer cell growth. 1243 17

Metastasis of prostate cancer to bone is a common complication of progressive prostate cancer. Skeletal metastases are often associated with severe pain and thus demand therapeutic interventions. Although often characterized as osteoblastic, prostate cancer skeletal metastases usually have an underlying osteoclastic component. Advances in osteoclast biology and pathophysiology have led toward defining putative therapeutic targets to attack tumor-induced osteolysis. Several factors have been found to be important in tumor-induced promotion of osteoclast activity. One key factor is the protein receptor activator of nuclear factor-kappa B ligand (RANKL), which is required to induce osteoclastogenesis. RANKL is produced by prostate cancer bone metastases, enabling these metastases to induce osteolysis through osteoclast activation. Another factor, osteoprotegerin, is a soluble decoy receptor for RANKL and inhibits RANKL-induced osteoclastogenesis. Osteoprotegerin has been shown in murine models to inhibit tumor-induced osteolysis. In addition to RANKL, parathyroid hormone-related protein and interleukin-6 are produced by prostate cancer cells and can promote osteoclastogenesis. Finally, matrix metalloproteinases (MMPs) are secreted by prostate cancer cells and promote osteolysis primarily through degradation of the nonmineralized bone matrix. MMP inhibitors have been shown to diminish tumor establishment in bone in murine models. Thus, many factors derived from prostate cancer metastases can promote osteolysis, and these factors may serve as therapeutic targets. The importance of osteoclasts in the establishment and progression of skeletal metastases has led to clinical evaluation of therapeutic agents to target them for slowing metastatic progression. Bisphosphonates are a class of compounds that decrease osteoclast life span by promoting their apoptosis. The bisphosphonate pamidronate has proven clinical efficacy for relieving bone pain associated with breast cancer metastases and has a promising outlook for prostate cancer metastases. Another bisphosphonate, zoledronic acid, appears to directly target prostate cancer cells in addition to diminishing osteoclast activity at the metastatic site. In addition to bisphosphonates, other novel therapies based on studies that delineate mechanisms of skeletal metastases establishment and progression will be developed in the near future.
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PMID:The role of osteoclastic activity in prostate cancer skeletal metastases. 1253 87

The role of interleukin-6 (IL-6) in the growth of an androgen-independent prostate cancer cell line (PC-3 m) was defined and the effect of dexamethasone, which was previously shown to modulate IL-6/IL-6 receptor (IL-6R) on this procedure was investigated. By using a pretty sensitive and specific enzyme immunoassay (ELISA), it was found that PC-3 m produced certain IL-6, but there was no difference in IL-6 secretion between the group with or without dexamethasone treatment. It was also found that PC-3 m cells could not be stimulated to grow by exogenous IL-6 (P > 0.05), while it could be inhibited to grow by anti-IL-6 monoclonal antibody and dexamethasone with a dose-dependent fashion. Our observation indicated that IL-6 acted as an autocrine growth factor for PC-3 m, and dexamethasone could inhibit cell proliferation by a mechanism independent of its effect on IL-6 mRNA expression.
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PMID:The effect of interleukin-6 on the proliferation of prostate cancer cells in vitro and the modulation of this procedure. 1253 83

Thrombin generation is increased in men with advanced prostate cancer. Thrombin has the ability to interact with, and affect the biology of, a variety of cell types including prostate cancer cell lines. We therefore looked for correlations between thrombin generation and other markers of disease activity in spot urine samples obtained from men with advanced prostate cancer. Excretion of part of the prothrombin activation peptide F(1+2) (called here iF2), interleukin-6 (IL-6), the bone turnover marker deoxypyridinoline (DpD), and vascular endothelial growth factor (VEGF) were quantitated in spot urine samples collected from 37 men with hormone-refractory prostate cancer. Following log transformation of the data, significant correlations were found by univariate analysis between the excretion of a marker of thrombin generation (iF2) and IL-6, DpD and VEGF, as well as between IL-6 and DpD or VEGF excretion. No correlation was found between any marker and serum PSA level. After multivariate analysis, a significant correlation remained between thrombin generation and IL-6 excretion. Analysis of a second urine specimen obtained from 19 of the subjects 1 to 7 months after the first also revealed a significant correlation between thrombin generation and IL-6, DpD, and VEGF excretion. These data provide evidence of a correlation between thrombin generation/coagulation system activation and IL-6 generation in patients with cancer. They provide a rationale for studying the effects of inhibitors of thrombin generation upon the biology of prostate cancer.
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PMID:Correlates of thrombin generation in patients with advanced prostate cancer. 1254 Sep 69

Interleukin-6 (IL-6) is a multifunctional cytokine that activates the signaling pathways of Janus kinases-signal transducers and activators of transcription (STAT) and/or mitogen-activated protein kinases (MAPK) in various tumors. Thus, it modulates cell growth and apoptosis. IL-6 levels are elevated in tissues and sera from prostate cancer patients and IL-6 receptor expression has been detected in prostate cancer cell lines and clinical specimens. Continuous exposure of prostate cancer cells to IL-6 might alter their responsiveness to this cytokine. To gain more insight into the function of IL-6 in prostate carcinoma, we have inoculated LNCaP-IL-6+ cells, generated after prolonged treatment with IL-6, into nude mice (total n = 16, two independent experiments). Controls included animals bearing LNCaP-IL-6- cells, passaged at the same time as LNCaP-IL-6+ cells without supplementation of IL-6. LNCaP-IL-6+ tumor volumes were larger than those of their counterparts at all time points. There were no signs of cachexia in any of the experimental animals and all mice were free of metastases. To better understand the mechanisms responsible for accelerated growth of LNCaP-IL-6+ tumors, we have investigated the expression of cell-cycle regulatory molecules by Western blot analysis. The levels of cyclin-dependent kinase 2 were elevated in LNCaP-IL-6+ cells. There was a strong down-regulation of cyclins D1 and E in the LNCaP-IL-6+ subline. The cell-cycle inhibitor p27 was expressed at a low level in LNCaP-IL-6+ cells and could not be up-regulated by addition of IL-6. Most notably, LNCaP-IL-6+ cells exhibited a reduced expression of the hypophosphorylated form of the retinoblastoma protein (pRb). Accelerated tumor growth in our model system was also associated with alterations in IL-6-signaling pathways. The ability of IL-6 to induce tyrosine phosphorylation of STAT3 was abolished in the LNCaP-IL-6+ subline. In contrast, the levels of the MAPK extracellular signal-regulated kinases 1/2 increased in cells generated after long-term IL-6 treatment. The inhibitor of MAPK kinase PD 98059 retarded the proliferation of LNCaP-IL-6+ but not that of control cells. In summary, we show in the present study that chronic exposure of prostate cancer cells to IL-6 facilitates tumor growth in vivo by abolishment of the growth control by pRb and activation of the MAPK signaling pathway. These findings could be relevant to understand the role of IL-6 in prostate cancer progression.
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PMID:Accelerated in vivo growth of prostate tumors that up-regulate interleukin-6 is associated with reduced retinoblastoma protein expression and activation of the mitogen-activated protein kinase pathway. 1254 23

Since the growth of prostate cancer is androgen-sensitive, metastatic disease has been treated by hormonal therapy. Almost all prostate cancer patients initially respond to hormonal therapy, but the majority gradually develop resistance. The mechanism of the change in tumors from being androgen-responsive to androgen-unresponsive is generally explained by clonal selection, adaptation, an alternative pathway of signal transduction and androgen receptor (AR) involvement. Since androgen action is mediated by ARs, abnormalities in ARs are believed to play an important role in the progression of prostate cancer. Hyperactivated AR gene mutations have been detected in 20-30% of hormone-refractory tumors and functional analyses have demonstrated a wide responsiveness to estrogens, progesterone and anti-androgens as well as to androgens. The AR is highly amplified in 30% of patients with hormone-refractory prostate cancer that has been treated by castration without anti-androgens. Immunohistochemical studies of ARs in hormone-refractory prostate cancer specimens have shown that AR protein is down-regulated. DNA hypermethylation of the AR promoter region leading to AR down-regulation has been identified in 30% of hormone-refractory prostate cancers. The AR N-terminal domain in the LNCaP cell line model is activated by interleukin-6 via mitogen-activated protein kinase and single transducers and activators of transcription 3. Epidemiological observations have shown that short CAG repeats are more frequently associated with higher transactivational function in the African-American population, which may explain racial differences in the incidence of prostate cancer. Among Japanese, a short CAG repeat appears to predict a response to hormonal therapy, indicating a positive prognostic value and good prognosis at the metastatic stage of prostate cancer. Several co-factors between ARs and the transcriptional complex have been cloned and reports indicate that steroid receptor co-activator 1 is correlated with the hormone-refractory progression of prostate cancer. Thus, ARs plays an important role in the progression of prostate cancer. Based on the findings described above, genetic diagnosis and/or molecular-targeted therapy via AR pathways can be developed for hormone-refractory states.
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PMID:Androgen receptor involvement in the progression of prostate cancer. 1279 Jul 84

Prostate cancer is one of the leading causes of death among men in the United States, and acquisition of hormone resistance (androgen independence) by cancer cells is a fatal event during the natural history of prostate cancer. Obesity is another serious health problem and has been shown to be associated with prostate cancer. However, little is known about the molecular basis of this association. Here we show that factor(s) secreted from adipocytes stimulate prostate cancer cell proliferation. Leptin is one of the major adipose cytokines, and it controls body weight homeostasis through food intake and energy expenditure. We identify leptin as a novel growth factor in androgen-independent prostate cancer cell growth. Strikingly, leptin stimulates cell proliferation specifically in androgen-independent DU145 and PC-3 prostate cancer cells but not in androgen-dependent LNCaP-FGC cells, although both cell types express functional leptin receptor isoforms. c-Jun NH2-terminal kinase (JNK) has been shown recently to play a crucial role in obesity and insulin resistance. Intriguingly, leptin induces JNK activation in androgen-independent prostate cancer cells, and the pharmacological inhibition of JNK blocked the leptin stimulation of androgen-independent prostate cancer cell proliferation. This suggests that JNK activation is required for leptin-mediated, androgen-independent prostate cancer cell proliferation. Furthermore, other cytokines produced by adipocytes and critical for body weight homeostasis cooperate with leptin in androgen-independent prostate cancer cell proliferation: interleukin-6 and insulin-like growth factor I demonstrate additive and synergistic effects on the leptin stimulation of androgen-independent prostate cancer cell proliferation, respectively. Therefore, adipose cytokines, as well as JNK, are key mediators between obesity and hormone-resistant prostate cancer and could be therapeutic targets.
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PMID:Prostate cancer cell-adipocyte interaction: leptin mediates androgen-independent prostate cancer cell proliferation through c-Jun NH2-terminal kinase. 1290 51

Data on the dural invasiveness of pituitary adenomas have been correlated to the expression of matrix metalloproteinases (e.g. MMP-9). Serine proteases have not yet been investigated in human pituitary adenomas. In this study, paraffin-embedded material from 84 human pituitary adenomas (acromegaly n=18, Cushing's disease n=21, prolactinoma n=18, thyroid-stimulating hormone-secreting adenoma n=1, nonsecreting adenoma n=26) and 9 nontumourous anterior pituitary lobes (obtained from patients with prostate cancer) was immunohistochemically analysed for expression of MMP-2, MMP-9, tissue inhibitor of metalloproteinases-2 (TIMP-2), urokinase-type plasminogen activator (uPA), uPA receptor (uPAR), tissue-type plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1), and interleukin-6 (IL-6). Cavernous sinus invasion was determined by assessment of preoperative magnetic resonance imaging and intraoperative inspection (invasive n=50, noninvasive n=34). In pituitary adenomas, reactions were positive (diffuse expression) to MMP-2 (74% of cases), MMP-9 (49%), TIMP-2 (88%), uPA (89%), uPAR (90%), tPA (69%), and PAI-1 (87%). A weak expression of IL-6 was found in 12% of the adenomas. All reactions were positive (focal expression) in every sample of anterior lobe tissue, except for uPA (negative in 3 out of 9 cases), and IL-6 (faintly positive in 5 out of 8 cases). Adenomas showed remarkably greater expression of uPA than anterior lobe tissue (Chi-square P<0.05). Nonsecreting adenomas exhibited a stronger tendency towards overexpression of uPA in invasive tumours when compared to noninvasive adenomas (Chi-square P=0.053). We found no correlation of MMP-9 expression and tumour invasion. TIMP-2 was overexpressed in noninvasive as compared to invasive adenomas (Chi-square P<0.05). The interrelationship between MMPs and serine proteinases in pituitary adenomas remains to be elucidated. From our data, a correlation between IL-6 and an activation of MMP-9 cannot be proven. The uPA-system may, however, play a role in dural invasion of pituitary adenomas.
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PMID:Expression of serine proteases and metalloproteinases in human pituitary adenomas and anterior pituitary lobe tissue. 1290 90

Androgen receptor (AR) is expressed in nearly all prostate cancers, including treatment-refractory disease. The role of this receptor in the molecular endocrinology of prostate cancer has become increasingly clear in recent years. The AR is now known to participate in tumor progression through 3 mechanisms: expression (activation and upregulation of receptor activity), point mutations, and ligand-independent activation. With regard to the latter mechanism, interleukin-6 (IL-6) is among the most important nonsteroidal regulators of AR activity. In the absence of androgen, IL-6 causes activation of AR that is approximately 50% of the maximal activity induced by androgen. At low concentrations of androgen, IL-6 and androgen synergistically activate AR. Nonsteroidal antiandrogens usually antagonize this activation, but they switch to an agonist effect in the presence of oncostatin M, an IL-6-related cytokine. The growth of parental LNCaP cells is initially inhibited by exposure to IL-6, but long-term treatment renders the cells resistant to such inhibition and confers a growth advantage. Both IL-6 and oncostatin M stimulate AR activity, but only oncostatin M is associated with strong acquisition of the agonist properties of nonsteroidal antiandrogens. It is hoped that continuing research on AR expression and function in prostate cancer will pave the way for new therapeutic strategies.
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PMID:Role of the androgen receptor axis in prostate cancer. 1460 14

Interleukin-6 (IL-6) and its receptor have been implicated in prostate cancer progression. Because other members of the IL-6 family such as leukaemia inhibitory factor (LIF) and oncostatin M (OSM) share gp130, the signal transduction subunit of their receptors, interpretation of the data without considering the expression of these cytokines and their specific receptor subunits could be misleading. The immunohistochemical pattern of the IL-6 family and their receptor subunits in normal prostate, benign prostatic hyperplasia (BPH), and prostatic carcinoma (PC) was investigated. In normal prostates, gp130 and OSMRalpha were detected exclusively in the stroma and LIFRbeta was very scarce. While IL-6 was scarcely immunolocalized to the basal cells of the epithelium, OSM was detected in the stroma and LIF in both the epithelium and the stroma. This suggests an autocrine role for this family of cytokines in the stroma of normal prostates. In BPH, gp130 and OSMRalpha were detected both in the epithelium and in the stroma, whereas LIFRbeta was localized only to the epithelium. IL-6 localized preferentially to the epithelium, OSM to the stroma, and LIF to both compartments. Therefore, in addition to the autocrine role in the stroma, IL-6 and OSM may play a paracrine role from the stroma to the epithelium in BPH. In PC, gp130 and OSMRalpha were detected both in the epithelium and in the stroma, increasing with rising Gleason grade, whereas LIFRbeta was localized exclusively to the epithelium of low Gleason grade carcinomas. IL-6, LIF, and OSM localized in all cell types, with immunostaining increasing with Gleason grade. These data suggest an autocrine role for these cytokines in the epithelial cells of PC. The distinct pattern of expression of LIFRbeta exclusively in low Gleason grade carcinomas makes LIFRbeta a candidate for malignancy diagnosis. The role of OSM mainly in high Gleason grade carcinomas makes OSM a putative target for prostate cancer therapy.
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PMID:Immunohistochemical analysis of the IL-6 family of cytokines and their receptors in benign, hyperplasic, and malignant human prostate. 1469 20

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