Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have identified a new antiproliferative activity from the conditioned medium of two androgen-independent prostatic cancer cell lines, PC3 and DU-145. This antiproliferative activity selectively inhibited cell proliferation of an androgen-dependent prostate cancer cell line LNCaP in a dose-dependent manner. No antiproliferative activity was observed against mouse fibroblast 3T3, normal human lymphocytes, human leukemic cells, including promyelocyte HL-60 or T cell HUT-78, or human adenocarcinoma cell lines, including prostatic cells JCA-1, ovary NIH:OVCAR-3, cervix C-33A, or breast MDA-MB-231. Cell cycle analysis revealed that the antiproliferative activity did not induce apoptosis in LNCaP cells, but it prevented some G1 LNCaP cells from entering into the S phase of the cell cycle. The antiproliferative activity was sensitive to high temperature (100 degrees C) and to proteinase digestion; however, it was resistant to 56 degrees C, pH 2.0, and reducing agent treatment, as well as to DNase and RNase digestion. The antiproliferative activity was partially purified by gel filtration, ion-exchange chromatography, and SDS-PAGE, with an apparent molecular weight of 50 kD. The antiproliferative activity was not affected by neutralizing antibody against TGF-beta 1,2,3, TNF-alpha, PDGF, EGF, IL-1, IL-2, IL-3, IL-4, or IL-6.
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PMID:Antiproliferative effect of a prostatic cell-derived activity on the human androgen-dependent prostatic carcinoma cell line LNCaP. 859 Mar 22

To understand specific interactions between stromal cells and epithelial cells in benign prostatic hyperplasia (BPH) and prostatic adenocarcinoma, we developed stromal-cell cultures from normal human prostate (PNX) and BPH (BH101), composed of fibroblasts and myofibroblasts. Their role in epithelial-cell growth was studied using the established cancer cell lines LNCaP, PC3 and DU145 and an SV40 large T-immortalized normal epithelial-cell line, PNT1A, in double-diffusion co-culture chambers. PNT1A was stimulated by PNX (x1.6) and more strongly by BH101 stromal cells (x2.7). Conversely, LNCaP growth decreased by 50% in the presence of BH101 stromal cells (stromal/epithelial ratio: 10). A BH101-conditioned medium (CM), obtained in serum-free conditions, induced 90% inhibition of [3H]thymidine incorporation of the LNCaP androgen-sensitive cell line. Two other androgen-independent prostate cancer cell lines were either insensitive to BH101 CM (PC3) or slightly inhibited (40% for DU145). BH101 produced large amounts of IL-1beta, IL-6 and IL-8. HPLC gel filtration enabled separation of an inhibitory fraction which contained IL-6. IL-6 was demonstrated to be responsible for the strong inhibitory effect since an IL-6-neutralizing antibody abolished this inhibition, which was reproduced by human recombinant IL-6. Recombinant IL-6 growth inhibition was observed only on LNCaP prostate cancer androgen-sensitive cells.
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PMID:Stromal cells from human benign prostate hyperplasia produce a growth-inhibitory factor for LNCaP prostate cancer cells, identified as interleukin-6. 890 Apr 30

The extensive mortality and morbidity associated with prostate cancer is caused by the high prevalence of metastatic disease at the time of diagnosis. The area most frequently involved in metastatic prostate cancer is the skeleton. Unlike other cancers, which metastasize to bone and destroy the bone matrix, prostate cancer is unique in that it is osteogenic, resulting in the formation of dense, sclerotic bone with high levels of osteoblastic activity. We proposed that factors produced by bone cells may be responsible for the development of prostate carcinoma metastasis. We studied the effects of these growth factors on prostate cell proliferation by [3H]thymidine incorporation and chemotaxis by the double-filter chamber method. Three prostate carcinoma cell lines were studied, LNCaP (androgen responsive) and PC-3 and DU-145 (androgen unresponsive). The bone-associated growth factors tested were: insulin-like growth factors I and II (IGF-I, IGF-II), transforming growth factor beta, interleukin (IL)-1 beta, IL-6, and tumor necrosis factor alpha (TNF-alpha), IGF-I and IGF-II significantly increased proliferation in all three cell lines, whereas IL-6, TNF-alpha, and IL-1 beta significantly decreased proliferation. Transforming growth factor beta induced a biphasic response in proliferation in DU-145 and PC-3 cells and produced no response on LNCaP cells. Increased cell chemotaxis occurred in the presence of IGF-I and IGF-II, and decreased cell chemotaxis occurred with the addition of TNF-alpha and IL-1 beta. These data indicate that growth factors produced by bone cells alter prostate carcinoma cell proliferation and chemotaxis and suggest that modulations of the production of these factors may be a potential therapeutic intervention in deterring the metastasis of prostate carcinoma to bone.
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PMID:The effects of growth factors associated with osteoblasts on prostate carcinoma proliferation and chemotaxis: implications for the development of metastatic disease. 904 21

Cytokines are known to modulate the level of both phase 1 and phase 2 drug-metabolizing enzymes in hepatocytes. Although the effects of cytokines on cytochrome P450 (CYP450) enzymes are well understood, there is limited knowledge on how cytokines may affect steroid UDP-glucuronosyltransferase (UGT) phase 2 enzyme activity and expression in different cell types, including hepatocytes and steroid target cells. LNCaP cells, which is a human prostate cancer cell line, is a good model to study the effect of cytokines in steroid target cells because it is known to express steroidogenic enzymes, including UGT2B15 and UGT2B17, which are widely expressed steroid UGT enzymes known to conjugate androgens. In this study, we examined the possible interaction among interleukin-1alpha (IL-1alpha), IL-4, IL-6, and steroid UGT enzymes (UGT2B15 and UGT2B17). Treatment of LNCaP cells with IL-1alpha led to a dose-dependent inhibition of dihydrotestosterone (DHT) glucuronidation. IL-1alpha decreased both UGT activity and LNCaP cell proliferation in the absence and presence of DHT (0.5 nM); a maximal inhibition of 70% was observed. IL-6 inhibited LNCaP cell proliferation as well as the DHT-induced proliferation of these cells. However, neither IL-4 nor IL-6 significantly affected the formation of DHT glucuronide. Ribonuclease protection and Western blot analyses demonstrated a specific reduction of UGT2B17 transcript and protein levels in IL-1alpha-treated LNCaP cells. The level of UGT2B15 was not affected by cytokine treatments, indicating a differential regulation between these two UGT enzymes. Transfection experiments performed with the UGT2B17 gene promoter region indicates that the regulation occurs at the transcription level via putative cis-acting elements. This study indicates that cell proliferation and UGT expression in steroid-responsive cancer cells are differentially regulated depending on the cytokines present in the cell microenvironment.
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PMID:Effect of interleukins on UGT2B15 and UGT2B17 steroid uridine diphosphate-glucuronosyltransferase expression and activity in the LNCaP cell line. 956 48

Cancer is consistently associated with anorexia. The Lobund-Wistar rat model of prostate cancer exhibits clinical manifestations (including anorexia) that resemble many aspects of the human disease. Cytokines are proposed to be involved in cancer-associated anorexia. Here we investigated mRNA profiles of feeding-modulatory cytokines and neuropeptides in specific brain regions of anorectic Lobund-Wistar rats bearing prostate adenocarcinoma tumor cells. Interleukin (IL)-1beta system components (ligand, signaling receptor, receptor accessory proteins, receptor antagonist), tumor necrosis factor-alpha, transforming growth factor-beta1, glycoprotein 130 (IL-6 receptor signal transducer), proopiomelanocortin (POMC, opioid peptide precursor), and neuropeptide Y (NPY) mRNAs were analyzed with sensitive and specific RNase protection assays. The same brain region sample was assayed for all components. The data show that early anorexia in tumor-bearing rats was associated with an upregulation of IL-1beta mRNA in the brain regions examined (cerebellum, cortex, and hypothalamus). IL-1 receptor antagonist (IL-1Ra) mRNA and IL-1 receptor type I mRNA levels were also significantly increased in the cortex and hypothalamus. All other cytokine components, POMC, or NPY mRNA levels were not significantly different between tumor-bearing and pair-fed (control) rats. IL-1beta mRNA and IL-1Ra mRNA were also significantly upregulated in the spleen of tumor-bearing rats. These data suggest that 1) IL-1beta mRNA upregulation in the brain may be relevant to the anorexia exhibited by the tumor-bearing Lobund-Wistar rat and 2) in vivo characterization of cytokine components in discrete brain regions during cancer is necessary to understand underlying molecular mechanisms responsible for cancer-associated neurological manifestations.
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PMID:Brain cytokine mRNAs in anorectic rats bearing prostate adenocarcinoma tumor cells. 968 94

Neuroendocrine differentiation in prostate cancer has received much attention recently because it has been found to be associated with androgen independence and shortened patient survival in some studies. We have investigated the effect of the cytokines interleukin-1 (IL-1), IL-2, and IL-6 on the expression of the neuroendocrine marker chromogranin A in human prostate cancer cell lines. Chromogranin A was measured by fluorescence-immunoassay, as well as by immunoblotting. We find that IL-1beta and IL-6 increase the cellular content and chromogranin A secretion by LNCaP and DU-145 cells. By contrast, IL-2 decreases the cellular and secreted chromogranin A levels in the two cell lines. Our results suggest that these proinflammatory cytokines can influence neuroendocrine differentiation in prostate cancer and be involved in disease progression.
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PMID:Modulation of neuroendocrine differentiation in prostate cancer by interleukin-1 and -2. 969 Jun 61

We have examined the effects that dexamethasone (DEX), alone or in combination with doxorubicin (DOX), cisplatin (CDDP), or etoposide (VP-16), exerts on the growth of the androgen-independent prostate cancer PC-3 cells. DEX exhibited only a limited cytotoxicity (growth inhibition of about 28% or 20% after 24 or 72 h of exposure, respectively, in the range of DEX 10-100 nM) and did not induce apoptosis in the cells. This cytotoxicity of DEX was mimicked by an active peptide (peptide Ac2-26) drawn from the human lipocortin 1 N-terminus region and abrogated by an antibody to human lipocortin 1. Two inhibitors of arachidonic acid metabolism, tenidap and indomethacin, also caused cytotoxicity. The cytotoxic effects of DEX in combination with DOX, CDDP, or VP-16 were antagonistic when the steroid was administered 3 h before or simultaneously with the drugs. Other schedule-dependency experiments further clarified that, at least in the case of the combination with DOX, it is the steroid that desensitizes the cells to the drug. When peptide Ac2-26, tenidap, or indomethacin were tested in combination with DOX, antagonism was also observed. DEX treatment neither modified the ability of the cells to accumulate DOX nor changed their weak expression of P-glycoprotein. PC-3 cells also produce IL-6, which autocrinally stimulates their growth, and whose gene expression may be reduced by glucocorticoids. In the present experiments DEX only slightly decreased the production and secretion of IL-6 by the cells. The present findings suggest that the slight cytotoxic activity and the drug resistance effects of DEX on PC-3 cells are mediated by induction of lipocortin 1 and inhibition of arachidonic acid metabolism, with no relationship to downregulation of IL-6 levels. These findings indicate also that the combination of DEX with conventional chemotherapeutic agents may result in antagonistic antitumor effects.
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PMID:Dexamethasone-induced cytotoxic activity and drug resistance effects in androgen-independent prostate tumor PC-3 cells are mediated by lipocortin 1. 980 59

Increasing evidence indicates that endothelin 1 (ET-1) is implicated in prostate tumour progression. However, data on ET-1 regulation in human prostate and prostate cancer cell lines are lacking. In this study, regulation of ET-1 and its precursor big ET-1, using PC3 cells, a human bone metastatic prostatic carcinoma cell line, was addressed. ET-1 and big ET-1 assays demonstrated greater secretion of both peptides in the presence of 10% fetal calf serum (FCS) as compared with 0.5% FCS. Incubation of PC3 cells in the absence and presence of various cytokines and growth factors known to be implicated in prostate stroma-epithelium interactions, revealed that IL-6, FGF7/KGF and FGF2/bFGF had no effect on ET-1 and big ET-1 secretion, whereas interleukin 1beta (IL-1beta), tumour necrosis factor alpha (TNF-alpha) and transforming growth factor beta (TGF-beta) stimulated their secretion in a concentration-dependent manner. Binding experiments indicated the presence of specific ET-1 receptors in PC3 cells: Kdapp = 1.1 x 0.2 x 10(-10)M, Bmax = 2660 +/- 390 sites/cell. Data analysis demonstrated the presence of only the ETA receptor subtype in PC3 cells. In conclusion, our results indicate that the implication of ET-1 in prostate cancer is likely to be mediated via paracrine/autocrine control of cell factors.
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PMID:Upregulation of endothelin 1 and its precursor by IL-1beta, TNF-alpha, and TGF-beta in the PC3 human prostate cancer cell line. 1008 38

The cell-cell interactions between tumor cells and stromal cells are considered to be important in the regulation of tumor development at primary and metastatic secondary sites. We studied the effects of various cytokines on the cell-cell interactions between androgen-dependent LNCaP or androgen-independent PC-3 human prostate cancer cell lines and normal fibroblasts using a co-culture system. Among the tested combinations of cytokines and fibroblasts, strong modulations of cytokine actions were seen in coculture with human normal fibroblasts WI-38. While interleukin (IL)-1beta or tumor necrosis factor-alpha (TNF-alpha) partially suppressed LNCaP cell growth in monoculture, each cytokine completely inhibited it in the case of coculture with WI-38 cells. On the other hand, they did not inhibit PC-3 cell growth significantly, regardless of monoculture or coculture. Conditioned medium prepared from WI-38 cells pretreated with IL-1beta or TNF-alpha also strongly inhibited LNCaP cell growth. In the conditioned medium, marked IL-6 secretion was induced from WI-38 cells by IL-1beta or TNF-alpha. Furthermore, neutralizing antibodies to IL-6 or IL-6 receptor abrogated the antiproliferative effects of IL-1beta- and TNF-alpha-pretreated WI-38 conditioned medium. These results demonstrate that the antiproliferative effects of IL-1beta and TNF-alpha on prostate cancer cells are enhanced by coculture with normal fibroblasts through some diffusible factor(s), such as IL-6, from the stimulated fibroblasts.
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PMID:Enhancement of antiproliferative effects of interleukin-1beta and tumor necrosis factor-alpha on human prostate cancer LNCaP cells by coculture with normal fibroblasts through secreted interleukin-6. 1039 Oct 95

Urokinase-type plasminogen activator (uPA) plays a central role in many aspects of cellular regulation, such as fibrinolysis, cell migration, and metastasis. The uPA induction by inflammatory stimuli such as IL-1, TNFalpha, and lipopolysaccharide (LPS) has been reported in a number of human cells. We examined the effects of LPS on uPA expression in human PC-3 prostatic cancer cells that express uPA in a conditioned medium. LPS increased the uPA accumulation in PC-3 cells, whereas IL-1, IL-6, and TNFalpha did not. Northern blot analysis revealed that the peak induction of uPA mRNA occurred 5 hours after LPS stimulation. A protein synthesis inhibitor, cycloheximide, amplified the LPS-induced uPA mRNA, suggesting that LPS induces uPA by activating the gene expression in which de novo protein synthesis is not necessary.
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PMID:Induction of urokinase-type plasminogen activator by lipopolysaccharide in PC-3 human prostatic cancer cells. 1070 10


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