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)

The clinical significance of serum interleukin-6 (IL-6) and its correlation with cystatin C (Cyst C), an endogenous inhibitor of cysteine proteinase cathepsin K, was investigated by immunoassays in patients with bone metastasis from breast cancer (BCa) or prostate cancer (PCa). Additional studies were also performed in these patients to assess the effects of zoledronic acid (ZA) administration on the circulating levels of these molecules. Mean IL-6 and Cyst C serum concentrations were significantly increased in BCa patients and in patients with primary osteoporosis (PO) compared to healthy subjects (HS). However, Cyst C, but not IL-6, resulted significantly more elevated in BCa patients than in PO patients. Furthermore, in BCa patients no correlation was highlighted between IL-6 and Cyst C or between these molecules and some clinicobiological parameters of malignant progression. Mean IL-6 levels were also higher in PCa patients and in patients with benign prostatic hyperplasia (BPH) than in HS while Cyst C resulted significantly higher in PCa but not in BPH patients as compared to HS. In PCa patients, a positive correlation was highlighted between IL-6 and number of bone metastases or serum prostate-specific antigen but not with the Gleason score. Conversely, Cyst C levels did not correlate with any of the parameters considered above or with IL-6. Receiver operating characteristic (ROC) curve analysis showed a poor diagnostic accuracy of IL-6 and Cyst C to detect BCa patients with skeletal metastases while, in PCa patients, only IL-6 showed a fair diagnostic performance in this respect. Finally, the administration of ZA to patients with bone metastases induced a statistically significant increase of serum IL-6 and Cyst C only PCa patients with bone metastasis. These data indicate that IL-6 and Cyst C may be regarded as novel targets for cancer treatment and as markers of increased osteoblastic activity associated to bisphosphonate treatments in PCa patients with bone metastases.
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PMID:Serum interleukin-6 in patients with metastatic bone disease: correlation with cystatin C. 1846 Dec 89

The proinflammatory cytokine interleukin-6 (IL-6) has been considered a positive growth factor in late stage prostate cancer (PC) cells and a potential target for therapeutic interference. We studied the effects of inhibition of IL-6 in LNCaP-IL6+ cells, a model system for advanced PC, which produce IL-6. By using the chimeric anti-IL-6 antibody, CNTO 328, we showed that the autocrine IL-6 loop is responsible for decreased sensitivity of LNCaP-IL-6+ cells to die by apoptosis. Dysregulation of Bcl-2 family members could be implicated in the acquisition of resistance to apoptosis in malignant cell lines. Myeloid cell leukemia 1 (Mcl-1) is an antiapoptotic member of this family that is overexpressed in the IL-6 selected cells compared with control. Specific knock-down of Mcl-1 gene expression by siRNA yielded an increase in apoptosis of LNCaP-IL-6+ cells. Interestingly, inactivation of IL-6 autocrine loop was not able to increase apoptosis levels in the absence of Mcl-1, thus suggesting this molecule as a mediator of the survival action of IL-6. Finally, using selective kinase inhibitors we provide evidence for the involvement of p38 and ERK1/2 mitogen-activated protein kinases pathways in the IL-6-mediated regulation of Mcl-1. In conclusion, these data suggest that endogenous IL-6 acts as an antiapoptotic factor in LNCaP-IL-6+ cells and that Mcl-1 is critical for its survival activity. CNTO 328, in our experimental conditions, is able to render LNCaP-IL-6+ cells more sensitive to apoptosis. These data support the concept of anti-IL-6 therapy in human PC.
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PMID:Mcl-1 is regulated by IL-6 and mediates the survival activity of the cytokine in a model of late stage prostate carcinoma. 1849 81

The cardio protective effect of estrogen in women has come under scrutiny as recent evidence from long-term trials has demonstrated negative findings. In contrast, the effect of endogenous sex hormones, specifically estrogen, on cardiovascular disease, inflammation and clotting parameters in men has not been well-studied. Men receiving androgen deprivation therapy for prostate cancer provide a unique model to study the effect of estrogen alone on inflammation and clotting factors. In a short-term randomized controlled trial of 17-beta estradiol (E(2)) versus placebo, we measured sex hormones, markers of inflammation including homocysteine (HC), C-reactive protein (CRP), interleukin-6 (IL-6) and coagulation factors including fibrinogen, plasminogen activator-inhibitor-1 (PAI-1) and anti-thrombin-III (AT-III) in 27 older men without bone metastases receiving androgen deprivation therapy or neoadjuvant treatment for prostate cancer. After 9 weeks of E(2) treatment, there was no difference in inflammation or clotting parameters between groups, but after 9 weeks of treatment AT-III increased in the E(2) treated group and decreased in the placebo group. CRP, homocysteine and IL-6 did not show any significant differences. We also evaluated the above parameters in 12 men 3 weeks after acute steroid withdrawal with androgen deprivation therapy and found no significant changes. We found an increase in AT-III in men receiving E(2) which may be related to gonadal steroid withdrawal, but no significant differences in other inflammatory or clotting factor parameters. While the current report is very preliminary in a small group of subjects, further studies are needed to determine the long-term effects of E(2) in this population of hypogonadal men.
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PMID:The effect of short-term estradiol therapy on clotting and inflammatory markers in older men receiving hormonal suppression therapy for prostate cancer. 1857 58

A novel prostate cancer cell line (PC-J) was isolated from an androgen independent non-prostate specific antigen (non-PSA) producing carcinoma cell line. The homologous correlation between PC-J and PC-3 was determined by short tandem repeat analysis. The PSA promoter activity was detected by transient expression assay in the PC-J and LNCaP cells but not in androgen insensitive PC-3 cells. When the PC-J cells were cotransfected with androgen receptor, androgen receptor coactivators and PSA reporter vector cells, the reporter assays indicated that nuclear receptor coactivator 4 (NCOA4) but not androgen receptor activator 24 (ARA24) increased the sensitivity and maximum stimulation of dihydrotestosterone (DHT)-inducing PSA promoter activity. The RT-PCR assays revealed that the expression of several tumor markers, including interleukin-6, prostate stem cell antigen (PSCA), prostate epithelium-specific Ets transcription factor (PDEF) and matriptase, was lower in the PC-J cells than in the PC-3 cells. This cell model elucidated the regulation of PSA expression and enabled comparison of the gene profile at different stages of metastasis in prostatic carcinoma.
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PMID:Prostate specific antigen gene expression in androgen insensitive prostate carcinoma subculture cell line. 1864 34

Recent studies have shown that naturally occurring compounds can enhance the efficacy of chemotherapeutic drugs. The objectives of this study were to investigate the molecular mechanisms by which diallyl trisulfide (DATS) enhanced the therapeutic potential of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in prostate cancer cells in vitro and on orthotopically transplanted PC-3 prostate carcinoma in nude mice. DATS inhibited cell viability and colony formation and induced apoptosis in PC-3 and LNCaP cells. DATS enhanced the apoptosis-inducing potential of TRAIL in PC-3 cells and sensitized TRAIL-resistant LNCaP cells. Dominant-negative FADD inhibited the synergistic interaction between DATS and TRAIL on apoptosis. DATS induced the expression of DR4, DR5, Bax, Bak, Bim, Noxa, and PUMA and inhibited expression of Mcl-1, Bcl-2, Bcl-X(L), survivin, XIAP, cIAP1, and cIAP2. Oral administration of DATS significantly inhibited growth of orthotopically implanted prostate carcinoma in BALB/c nude mice compared with the control group, without causing weight loss. Cotreatment of mice with DATS and TRAIL was more effective in inhibiting prostate tumor growth and inducing DR4 and DR5 expression, caspase-8 activity, and apoptosis than either agent alone. DATS inhibited angiogenesis (as measured by CD31-positive and factor VIII-positive blood vessels and hypoxia-inducible factor-1alpha, vascular endothelial growth factor, and interleukin-6 expression) and metastasis [matrix metalloproteinase (MMP)-2, MMP-7, MMP-9, and MT-1 MMP expression], which were correlated with inhibition in AKT and nuclear factor-kappaB activation. The combination of DATS and TRAIL was more effective in inhibiting markers of angiogenesis and metastasis than either agent alone. These data suggest that DATS can be combined with TRAIL for the prevention and/or treatment of prostate cancer.
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PMID:Diallyl trisulfide increases the effectiveness of TRAIL and inhibits prostate cancer growth in an orthotopic model: molecular mechanisms. 1872 80

Several groups, including ours, have reported that annexin A2 (ANXA2) expression is reduced in most prostate cancer (CaP). More recently, however, we reported that ANXA2 is expressed in some high-grade tumors, but the biologic consequence of this is currently unknown. To elucidate the function of ANXA2 in CaP, we reduced its expression in DU145 cells using shRNA and tested the impact on characteristics of malignancy. Reduction of ANXA2 suppressed anchorage-dependent and -independent cell growth without affecting invasiveness. Interestingly, interleukin-6 (IL-6) secretion was reduced concomitantly with the reduction of ANXA2 but independently of S100A10. IL-6 expression was restored when wild type but not mutant ANXA2 was reexpressed in these cells. In a retrospective study of radical prostatectomy specimens from patients with nonmetastatic CaP, 100% of patients with ANXA2-positive tumors (n = 4) had a biochemical relapse while only 50% of patients with ANXA2 negative tumors (n = 20) relapsed, suggesting that ANXA2 expression in prostate tumors may be predictive of biochemical relapse. Significant cytoplasmic staining of ANXA2 was detected in 3 of 4 ANXA2-positive tumors, whereas ANXA2 is localized to the plasma membrane in benign prostatic glands. These finding, taken together, suggests a possible mechanism whereby ANXA2 expression positively contributes to an aggressive phenotype in a subset of CaP and suggest that ANXA2 has markedly different functions depending on its cellular context. Finally, this is the first description of a role for ANXA2 in IL-6 expression, and ANXA2 represents a new therapeutic target for reducing IL-6 in high-grade prostate cancer.
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PMID:Annexin A2 positively contributes to the malignant phenotype and secretion of IL-6 in DU145 prostate cancer cells. 1892 33

It is hypothesized that ligand-independent activation of the androgen receptor is one of the mechanisms implicated in tumour progression. However, supportive evidence is limited to the effect of HER-2/neu that stimulates prostate cancer progression through activation of the androgen receptor. In the present study, we have asked whether the proinflammatory cytokine interleukin-6 (IL-6), which is known to stimulate androgen receptor activity and expression of its downstream target genes, may also induce growth of androgen-sensitive cells. We have found that IL-6 differentially regulates proliferation of LAPC-4 and MDA PCa 2b cells. In MDA PCa 2b cells, growth stimulation by IL-6 was reversed by administration of either the non-steroidal anti-androgen bicalutamide or the inhibitor of the mitogen-activated protein kinase pathway PD98059. Neither cell line was found to express endogenous IL-6. Interestingly, the treatment of those prostate cancer cells did not increase phosphorylation of STAT3. The effect of IL-6 on stimulation of androgen receptor activity in MDA PCa 2b cells was lower than that of androgen, comparable with findings reported by other researchers. However, growth of MDA PCa 2b xenografts in castrated animals treated with IL-6 was similar to that in non-castrated animals. In addition, bicalutamide showed an inhibitory effect on IL-6-regulated growth in vivo. Taken together, data in the present study demonstrate that IL-6 may cause growth of androgen receptor-positive tumours in vitro and in vivo through activation of the androgen receptor.
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PMID:Interleukin-6 stimulation of growth of prostate cancer in vitro and in vivo through activation of the androgen receptor. 1901 Oct 39

Men with androgen-independent prostate cancer (AIPC) frequently have bone metastasis. The effects of chemotherapy on markers of bone metabolism have not been well characterized. We conducted a prospective study of patients with AIPC randomized in the first cycle to receive either docetaxel/estramustine or zoledronic acid, a bisphosphonate, to inhibit osteoclastic activity. Here we report the effects of therapy on markers of bone metabolism in these patients following the first cycle of therapy. Serum levels of several indices of bone remodeling were evaluated using commercial enzyme-linked immunosorbent assays. Changes in markers of bone metabolism were compared in patients receiving initial chemotherapy versus bisphosphonate. There was no significant difference in median change in any of the measured bone markers in patients given zoledronic acid when compared to chemotherapy. When comparing responders to nonresponders, overall interleukin-6 (IL-6) decreased by 35% in prostate-specific antigen responders; whereas, IL-6 levels increased by 76% in nonresponders (p = 0.03). Elevated IL-6 levels and reductions in IL-6 levels early in treatment may reflect ultimate clinical response to docetaxel-based regimens.
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PMID:Change in markers of bone metabolism with chemotherapy for advanced prostate cancer: interleukin-6 response is a potential early indicator of response to therapy. 1901 38

Increasing evidence suggests that aberrant activation of the androgen receptor (AR) plays a pivotal role in the development and progression of androgen depletion-independent prostate cancer (PCa) after androgen deprivation therapy. Here, we show that loss of the PTEN tumor suppressor gene is associated with hyperactivation of the AR in human PCa cell lines. This effect is mediated primarily by its downstream effector FOXO1. In addition to the inhibition of androgenic activation of the AR, forced expression of FOXO1 in PTEN-negative PCa cells also inhibits androgen-independent activation of the AR in a manner independent of FOXO1 transcriptional function. In contrast, silencing of FOXO1 in PTEN-positive cells not only increases the basal activity of the AR in the absence of androgens, it also markedly sensitizes the AR activation by low levels of androgens or nonandrogenic factors such as interleukin-6. FOXO1-mediated inhibition of the AR is partially attenuated by the histone deacetylase (HDAC) inhibitor trichostatin A. Accordingly, FOXO1 interacts with HDAC3 as shown by coimmunoprecipitation assays, and cotransfection of cells with FOXO1 and HDAC3, but not HDAC1 and HDAC2, results in a greater inhibition of AR activity than in cells transfected with FOXO1 or HDAC3 individually. Together, our findings define a novel corepressor function of FOXO1 in inhibition of androgen-independent activation of the AR.
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PMID:A transcription-independent function of FOXO1 in inhibition of androgen-independent activation of the androgen receptor in prostate cancer cells. 1907 97

The critical role played by stroma-epithelium crosstalk in carcinogenesis and progression of prostate cancer has been increasingly recognized. These interactions are mediated by a variety of paracrine factors secreted by cancer cells and/or stromal cells. In human prostate cancer, reactive stroma is characterized by an increase in myofibroblasts and a corresponding amplification of extracellular matrix production and angiogenesis. Permanent genetic mutations have been reported in stromal cells as well as in tumour cells. Transforming growth factor-beta, vascular endothelial growth factor, platelet-derived growth factor and fibroblast growth factor signalling pathways are involved in the process of angiogenesis, whereas hepatocyte growth factor, insulin-like growth factor-1, epidermal growth factor, CXC12 and Interleukin-6 play active roles in the progression, androgen-independent conversion and distal metastasis of prostate cancer. Some soluble factors have reciprocal interactions with androgens and the androgen receptor (AR), and can even activate AR in the absence of the androgen ligand. In this article, we review the complex interactions between cancer cells and the surrounding microenvironment, and discuss the potential therapeutic targets in the stromal compartment of prostate cancer.
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PMID:Stroma-epithelium crosstalk in prostate cancer. 1909 34

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