Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P05231 (interleukin-6)
 23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The neuroendocrine (NE) cell is a minor cell population in normal human prostate glands. The number of NE cells is increased in advanced hormone-refractory prostate carcinomas (PCA). The mechanism of increased NE cell population in these advanced tumors is poorly understood. We examined molecular mechanisms which may be involved in the regulation of the transdifferentiation process of human PCA cells leading to a NE phenotype. We compared PCA cell lines LNCaP and PC-3 in the following medium conditions: steroid-reduced (SR), interleukin-6 (IL-6)-supplemented, or dibutyrate cAMP (db-cAMP)-supplemented. We found that androgen-responsive C-33 LNCaP cells responded to all treatments, having a neuronal-like morphology. In contrast, C-81 LNCaP cells, having a decreased androgen responsiveness, had a less pronounced effect although followed a similar trend. Androgen-unresponsive PC-3 cells showed little change in their morphology. Grown in the SR condition, the level of neuron-specific enolase (NSE), a marker of neuronal cells, was upregulated in C-33 LNCaP cells, while to a lesser degree in the presence of IL-6. In the presence of db-cAMP, the NSE level in C-33 cells was decreased, lower than that in control cells. An opposite effect was observed for C-81 LNCaP cells. Nevertheless, the NSE level was only elevated in db-cAMP-treated PC-3 cells, but no change was found in PC-3 cells grown in the SR- or IL-6-supplemented medium. Thus, a similar gross phenotypic change may correlate with differential molecular expressions. We also analyzed the expression of protein tyrosine phosphatase alpha (RPTPalpha) since it plays a critical role in normal neuronal differentiation and signaling. Our results showed that the expression of RPTPalpha correlates with the NE phenotypic change of LNCaP cells in the SR condition. In summary, our data clearly show that the molecular process by which cultured human prostate cancer cells undergo a transdifferentiation process to a NE cell-like phenotype is accompanied by differential expressions of different markers, and a gross NE cell-like phenotype can occur by exposing PCA cells to different pharmacological agents.
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PMID:Multipathways for transdifferentiation of human prostate cancer cells into neuroendocrine-like phenotype. 1138 66

Interleukin-6 (IL-6) induces prostate cancer (CaP) cell proliferation in vitro. Several lines of evidence suggest that IL-6 may promote CaP progression through induction of an androgen response. In this work, we explored whether IL-6 induces androgen responsiveness through modulation of androgen receptor (AR) expression. We found that in the absence of androgen, IL-6 increased prostate-specific antigen (PSA) mRNA levels and activated several androgen-responsive promoters, but not the non-androgen responsive promoters in LNCaP cells. Bicalutamide, an antiandrogen, abolished the IL-6 effect and IL-6 could not activate the PSA and murine mammary tumor virus reporters in AR-negative DU-145 and PC3 cells. These data indicate the IL-6 induces an androgen response in CaP cells through the AR. Pretreatment of LNCaP cells with SB202190, PD98059, or tyrphostin AG879 [p38 mitogen-activated protein kinase (MAPK), MAP/extracellular signal-regulated protein kinase kinase 1/2, and ErbB2 MAPK inhibitors, respectively) but not wortmannin (PI3-kinase inhibitor) blocked IL-6-mediated induction of the PSA promoter, which demonstrates that IL-6 activity is dependent on a MAPK pathway. Finally, IL-6 activated the AR gene promoter, resulting in increased AR mRNA and protein levels in LNCaP cells. These results demonstrate that IL-6 induces AR expression and are the first report of cytokine-mediated induction of the AR promoter. Taken together, our results suggest that IL-6 induces AR activity through both increasing AR gene expression and activating the AR in the absence of androgen in CaP cells. These results provide a mechanism through which IL-6 may contribute to the development of androgen-independent CaP.
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PMID:Interleukin-6 induces androgen responsiveness in prostate cancer cells through up-regulation of androgen receptor expression. 1141 May 19

Neuroendocrine (NE) differentiation in prostatic adenocarcinomas has been reported to be an early marker for development of androgen independence. Secretion of mitogenic peptides from nondividing NE cells is thought to contribute to a more aggressive disease by promoting the proliferation of surrounding tumor cells. We undertook studies to determine whether the prostate cancer cell line LNCaP could be induced to acquire NE characteristics by treatment with agents that are found in the complex environment in which progression of prostate cancer towards androgen independence occurs. We found that cotreatment of LNCaP cells with agents that signal through cyclic AMP-dependent protein kinase (PKA), such as epinephrine and forskolin, and with the cytokine interleukin-6 (IL-6) promoted the acquisition of an NE morphological phenotype above that seen with single agents. Convergent IL-6 and PKA signaling also resulted in potentiated mitogen-activated protein kinase (MAPK) activation without affecting the level of signal transducer and activator of transcription or PKA activation observed with these agents alone. Cotreatment with epinephrine and IL-6 synergistically increased c-fos transcription as well as transcription from the beta4 nicotinic acetylcholine receptor subunit promoter. Potentiated transcription from these elements was shown to be dependent on the MAPK pathway. Most importantly, cotreatment with PKA activators and IL-6 resulted in increased secretion of mitogenic neuropeptides. These results indicate that PKA and IL-6 signaling participates in gene transcriptional changes that reflect acquisition of an NE phenotype by LNCaP cells and suggest that similar signaling mechanisms, particularly at sites of metastasis, may be responsible for the increased NE content of many advanced prostate carcinomas.
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PMID:Interleukin-6- and cyclic AMP-mediated signaling potentiates neuroendocrine differentiation of LNCaP prostate tumor cells. 1171 82

Sex hormones have a broad range of actions in regulating very diverse systems through life as well as critical reproductive and growth processes. Sex hormone biology in its satisfaction of the early demands of species survival and reproductive advantage may be leading a destructive process resulting in frailty and the less desirable aspects of aging that may, in men, be termed andropause. One important system associated directly with aging is interleukin-6, which increases as androgens decline. This may be taking place regardless of androgen receptor activity. It is currently acknowledged that androgens are the first but not the only possible treatment for andropause. There is an acute appreciation of the potentially undesirable impact of androgens on the biology of prostate cancer, as well as, possibly, the cardiovascular system. Most authors agree that careful evaluation and surveillance of the prostate must attend androgen therapy in aging men.
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PMID:Andropause: coming of age for an old concept? 1173 96

The androgen receptor (AR) is a ligand-activated transcription factor that mediates the biological responses of androgens. However, non-androgenic pathways have also been shown to activate the AR. The mechanism of cross-talk between the interleukin-6 (IL-6) and AR signal transduction pathways was investigated in LNCaP human prostate cancer cells. IL-6 induced several androgen-response element-driven reporters that are dependent upon the AR, increased the phosphorylation of mitogen-activated protein kinase (MAPK), and activated the AR N-terminal domain (NTD). Inhibitors to MAPK and JAK decreased the IL-6-induced phosphorylation of MAPK and activation of the AR NTD. Immunoprecipitation and transactivation studies showed a direct interaction between amino acids 234-558 of the AR NTD and STAT3 following IL-6 treatment of LNCaP cells. These results demonstrate that activation of the human AR NTD by IL-6 was mediated through MAPK and STAT3 signal transduction pathways in LNCaP prostate cancer cells.
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PMID:Activation of the androgen receptor N-terminal domain by interleukin-6 via MAPK and STAT3 signal transduction pathways. 1175 84

Cyclooxygenase (COX)-2 expression and prostaglandin E(2) (PGE(2)) secretion are increased in prostatic intraepithelial neoplasia (PIN) and prostate cancer. PGE(2) biosynthesis by cyclooxygenase (COX)-2 plays a pivotal role in inflammation and carcinogenesis. One of the critical proinflammatory cytokines in the prostate is interleukin-6 (IL-6). We hypothesized that increased expression of COX-2, with resultant increased levels of PGE(2) in human PIN cells, activates the IL-6 signaling pathway. We demonstrate an autocrine upregulation of PGE(2) mediated by IL-6 in a human PIN cell line. We further demonstrate that PGE(2) stimulates soluble IL-6 receptor (sIL-6R) release, gp130 dimerization, Stat-3 protein phosphorylation, and DNA binding activity. These events, induced by PGE(2), lead to increased PIN cell growth. Treatment of PIN cells with a selective COX-2 inhibitor decreases cell growth. Finally, PGE(2)-stimulated PIN cell growth was abrogated by the addition of IL-6 neutralizing antibodies. These data provide mechanistic evidence that increased expression of COX-2/PGE(2) contributes to prostate cancer development and progression via activation of the IL-6 signaling pathway.
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PMID:Prostaglandin E(2) stimulates prostatic intraepithelial neoplasia cell growth through activation of the interleukin-6/GP130/STAT-3 signaling pathway. 1177 61

Transcription factor nuclear factor kappaB (NF-kappaB) controls gene expression of a number of genes, including cytokines such as interleukin-6 (IL-6), granulocyte-macrophage (GM)-CSF, and interleukin-8 (IL-8). IL-6 is known to play important roles in the growth of prostate cancer cells, activation of androgen receptor, and prostate-specific protein expression. NF-kappaB is activated by extracellular signals such as proinflammatory cytokines, chemotherapeutic reagents, and radiation. Here we demonstrate that cisplatin (CDDP) and etoposide (VP-16) induce nuclear translocation of NF-kappaB in prostate cancer cell lines, followed by secretion of IL-6. We also demonstrated that the growth of hormone-independent prostate cancer cell lines can be inhibited by the anti-NF-kappaB reagent N-acetyl-L-cysteine (NAC). These observations indicate that NF-kappaB can be a target of new adjuvant therapy against hormone refractory prostate cancer.
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PMID:N-acetyl-L-cysteine enhances chemotherapeutic effect on prostate cancer cells. 1194 26

The androgen receptor (AR) can be activated in the absence of androgens by interleukin-6 (IL-6) in human prostate cancer cells. The events involved in ligand-independent activation of the AR are unknown, but have been suggested to involve phosphorylation of the AR itself or a receptor-associated protein. Steroid receptor coactivator-1 (SRC-1) has been shown to interact with the human AR and to modulate ligand-dependent AR transactivation and is regulated by phosphorylation by MAPK. To date, no one has examined the role of SRC-1 in ligand-independent activation of the AR by IL-6 or other signaling pathways known to activate the full-length receptor. This study addressed this and has revealed the following. 1) SRC-1 similarly enhanced ligand-independent activation of the AR by IL-6 to the same magnitude as that obtained via ligand-dependent activation. 2) Androgen and IL-6 stimulated the MAPK pathway. 3) MAPK was required for both ligand-dependent and ligand-independent activation of the AR. 4) Phosphorylation of SRC-1 by MAPK was required for optimal ligand-independent activation of the AR by IL-6. 5) Protein-protein interaction between endogenous AR and SRC-1 was dependent upon treatment of LNCaP cells with IL-6 or R1881. 6) Protein-protein interaction between the AR N-terminal domain and SRC-1 was independent of MAPK. 7) Ligand-independent activation of the AR did not occur by a mechanism of overexpression of either solely wild-type SRC-1 or mutant SRC-1 that mimics its phosphorylated form.
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PMID:Ligand-independent activation of the androgen receptor by interleukin-6 and the role of steroid receptor coactivator-1 in prostate cancer cells. 1216 82

The androgen receptor (AR), a transcription factor that mediates the action of androgens in target tissues, is expressed in nearly all prostate cancers. Carcinoma of the prostate is the most frequently diagnosed neoplasm in men in industrialized countries. Palliative treatment for non-organ-confined prostate cancer aims to down-regulate the concentration of circulating androgen or to block the transcription activation function of the AR. AR function during endocrine therapy was studied in tumor cells LNCaP subjected to long-term steroid depletion; newly generated sublines could be stimulated by lower concentrations of androgen than parental cells and showed up-regulation of AR expression and activity as well as resistance to apoptosis. Androgenic hormones regulate the expression of key cell cycle regulators, cyclin-dependent kinase 2 and 4, and that of the cell cycle inhibitor p27. Inhibition of AR expression could be achieved by potential chemopreventive agents flufenamic acid, resveratrol, quercetin, polyunsaturated fatty acids and interleukin-1beta, and by the application of AR antisense oligonucleotides. In the clinical situation, AR gene amplification and point mutations were reported in patients with metastatic disease. These mutations generate receptors which could be activated by other steroid hormones and non-steroidal antiandrogens. In the absence of androgen, the AR could be activated by various growth-promoting (growth factors, epidermal growth factor receptor-related oncogene HER-2/neu) and pleiotropic (protein kinase A activators, interleukin-6) compounds as well as by inducers of differentiation (phenylbutyrate). AR function is modulated by a number of coactivators and corepressors. The three coactivators, TIF-2, SRC-1 and RAC3, are up-regulated in relapsed prostate cancer. New experimental therapies for prostate cancer are aimed to down-regulate AR expression and to overcome difficulties which occur because of the acquisition of agonistic properties of commonly used antiandrogens.
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PMID:Androgen receptors in prostate cancer. 1223 44

Prostate cancer (PCa) begins as an androgen-dependent tumor that will eventually progress to an androgen-independent stage after androgen ablation. Although little is understood about this transition to androgen independence, the androgen receptor (AR) appears to be involved. The coactivator p300 has been shown to interact with the AR during its androgen-dependent transactivation. We show that p300 is involved downstream of the mitogen-activated protein kinase pathway during transactivation of the AR by interleukin-6 (IL-6). Furthermore, we demonstrate that sequestration of p300 with E1A inhibits the IL-6-dependent transactivation of the AR, and that increasing amounts of p300 reverse this inhibition. A mutant p300 that lacks histone acetyltransferase (HAT) activity did not reverse E1A-mediated inhibition. By using small-interference RNA designed to target p300 transcripts, we demonstrate that, after silencing p300, there was no induction of AR activity by IL-6. These findings reveal a unique role for p300 and its HAT activity, indicating that it is necessary for the ligand-independent transactivation of the AR in androgen-independent PCa cells.
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PMID:p300 mediates androgen-independent transactivation of the androgen receptor by interleukin 6. 1238 15


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