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)

Epidemiological evidence strongly suggests that lycopene consumption contributes to prostate cancer risk reduction. Preclinical studies show that lycopene acts via different mechanisms, which have the potential to cooperate in reducing the proliferation of normal and cancerous prostate epithelial cells, in reducing DNA damage, and in improving oxidative stress defense. The mechanisms include inhibition of prostatic IGF-I signaling, IL-6 expression, and androgen signaling. Moreover, lycopene improves gap-junctional communication and induces phase II drug metabolizing enzymes as well as oxidative defense genes. These findings provide plausible explanations for the epidemiological findings how lycopene can contribute to reduced prostate cancer risk. The novel finding that lycopene reduces local androgen signaling in the prostate suggests also efficacy in prevention of benign prostate hyperplasia. Intervention trials in humans are required to finally prove clinical efficacy of the lycopene molecule in prostate health.
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PMID:Lycopene: modes of action to promote prostate health. 1600 47

Parathyroid hormone-related protein (PTHrP) is an oncoprotein that is expressed in many malignancies as well as normal tissues. At essentially every site of expression, PTHrP regulates cell growth and proliferation. We and other investigators have previously reported that PTHrP is widely expressed by prostate cancer. For this tumor, there are substantial in vitro and correlative data that PTHrP expression regulates the progression of the tumor, especially in bone, but little direct data. We studied the effects of PTHrP expression on prostate cancer behavior directly in a mouse model of human prostate cancer cells that were transfected to express different forms of the polypeptide and then injected intraskeletally. Skeletal progression of the prostate cancer cells was evaluated radiologically and by measurement of serum tumor markers. PTHrP transfection converted a non-invasive cell line into one that progressed in the skeleton: Injection of the PTHrP transfected cells resulted in greater tumor progression in bone when compared to non-transfected cells, and this effect was also influenced by non-amino terminal peptides of PTHrP. Serum measurements of PTHrP, IL-6, IL-8, and calcium reflected tumor burden. Our experiments provide direct in vivo evidence that PTHrP expression results in the skeletal progression of prostate cancer cells.
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PMID:Direct evidence that PTHrP expression promotes prostate cancer progression in bone. 1562 38

The mechanisms that regulate prostate cancer growth and proliferation are not fully understood. IL-6, a multifunctional cytokine, has been shown to play an important role in prostate cancer biology. Functional role of MAP-kinase signal transduction pathways in prostate biology has not been evaluated in detail. In the present study we evaluated the effects of modulation of p42/44 MAP kinase signal transduction pathway on IL-6 expression and secretion by PC3 cells, a line of hormone refractory prostate cancer cells. Results presented, herein, demonstrate that modulation of p42/44 MAP kinase activity results in partial inhibition of synthesis and secretion of IL-6. These data suggest that modulation of p42/p44 may result in regulation of other survival pathways as well.
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PMID:p42/p44 Mitogen-activated protein kinase signal transduction pathway regulates interleukin-6 expression in PC3 cells, a line of hormone-refractory prostate cancer cells. 1565 4

Neuroendocrine (NE) cells are found in prostate tumors, and their incidence is considered a promising prognostic indicator for the development of androgen-independent disease. NE cells are derived from non-NE prostate cancer cells and secrete factors that can act in a paracrine manner to stimulate the survival, growth, motility, and metastatic potential of prostatic carcinoma cells. Factors such as IL-6, epinephrine, and forskolin induce NE differentiation in prostate cancer cells; the mechanisms involve increases in intracellular cAMP, protein kinase A (PKA) activation and reduced intracellular calcium levels. Transcription factors implicated in the acquisition of NE characteristics by prostate cancer cells include STAT3, CREB, EGR1, c-fos, and NF-kappaB. Expression of Chromogranin A, neuron-specific enolase, bcl-2, and the androgen receptor are modulated during NE differentiation and serve as molecular markers for NE cells. Most importantly, NE cells secrete neuropeptides, such as bombesin, neurotensin, PTHrP, serotonin, and calcitonin, which trigger growth and survival responses in androgen-independent prostate cancer cells. Prostate cancer cell receptors that play a role in these processes include the gastrin-releasing peptide (GRP) receptor, neurotensin receptors, and the epidermal growth-factor receptor (EGFR). Signal-transduction molecules activated by these neuropeptides include Src, focal adhesion kinase (FAK), ERK, and PI3K/Akt, with subsequent activation of Elk-1, NF-kappaB, and c-myc transcription factors. A multitude of genes are then expressed by prostate cancer cells, which are involved in proliferation, anti-apoptosis, migration, metastasis, and angiogenesis. Targeting of these pathways at multiple levels can be exploited to inhibit the process by which NE cells contribute to the progression of androgen-independent, treatment-refractory prostate cancer.
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PMID:Neuroendocrine cells in prostate cancer. 1566 58

Prostate cancer is the second highest cause of cancer-related deaths of men in the US. Signal transducers and activators of transcription (STATs) proteins are a small family of latent cytoplasmic transcription factors that act downstream of Janus kinase (JAK) activation and mediate intracellular signaling from a wide variety of cytokines, growth factors, and hormones. Aberrant activation of STAT3 has been implicated in the progression of many human carcinomas, including prostate cancer. Previously, we have characterized a novel tyrosine kinase inhibitor peptide, Tkip, that is a mimetic of suppressor of cytokine signaling 1 (SOCS-1). Similar to SOCS-1, Tkip binds to the autophosphorylation site of JAK2 and inhibits phosphorylation of STAT1alpha. In this study, we determined the inhibitory effects of Tkip on the human prostate cancer cell lines DU145 and LNCaP. Tkip inhibited cellular proliferation of both DU145 and LNCaP cells, with a slightly greater antiproliferative effect on DU145 cells. Cell cycle analysis using flow cytometry showed Tkip blockage of progression into the S phase of the cell cycle. Tkip also inhibited constitutive (DU145) and IL-6-induced (LNCaP) activation of STAT3, consistent with the fact that STAT3 activation is mediated by JAK2. Tkip also slightly reduced the levels of cyclin D1, an important regulator of cell cycle progression into S phase, in DU145 and LNCaP cancer cell lines. These data describe a potentially important therapeutic that targets both constitutive and IL-6-induced STAT3 activation in human prostate cancer cell lines.
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PMID:A SOCS-1 peptide mimetic inhibits both constitutive and IL-6 induced activation of STAT3 in prostate cancer cells. 1568 10

1alpha,25-dihydroxyvitamin D3 (1alpha,25(OH)2D3 or calcitriol) is an active hormone that regulates cellular proliferation and induces apoptosis in cancer cells. Here we report on a new calcitriol target gene in prostate cancer cells, tumour necrosis factor alpha (TNF-alpha). Calcitriol and its analogue CB1093 up-regulate TNF-alpha mRNA expression in LNCaP and PC-3 cells. The stimulation is dose-dependent in both of these cell lines, demonstrated by the quantitative real-time polymerase chain reaction. Calcitriol and CB1093 act synergistically with human recombinant TNF-alpha in activation of TNF-alpha mRNA expression in LNCaP but not in PC-3 cells. Transcriptional activation of TNF-alpha gene by calcitriol or CB1093 does not lead to TNF-alpha protein secretion, however calcitriol and CB1093 enhance TPA-stimulated TNF-alpha production in LNCaP cells. We did not observe any significant effect of calcitriol on regulation of TNFR1 at the level of gene expression. Nor does calcitriol affect transcriptional regulation of cytokine (IL-1, IL-6) and cytokine receptor genes in LNCaP and PC-3 prostate cancer cell lines. Calcitriol and its analogue CB1093 at 10 nM concentration induce programmed cell death in LNCaP cells. Combined addition of human recombinant TNF-alpha with calcitriol or CB1093 cause enhanced effect in induction of apoptosis. We conclude that under physiological conditions vitamin D activates only the transcription of TNF-alpha gene, for TNF-alpha protein synthesis additional cofactors are required. Therefore a cooperation of vitamin D and TNF-alpha may play an important role in the control of cell growth in prostate cancer.
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PMID:Vitamin D-induced up-regulation of tumour necrosis factor alpha (TNF-alpha) in prostate cancer cells. 1590 73

Prostate cancer remains a leading cause of cancer illness and death among men in Europe. No curative treatment exists when the disease has spread beyond the prostate. Immunotherapy with DNA vaccines has emerged as a potential therapeutic approach for the induction of antitumor specific cytotoxic T lymphocytes. In this study six patients with hormone-refractory prostate cancer were monitored for their ability to mount PSA-specific cellular responses after receiving a pVAX/PSA DNA vaccine (patients 1-3, 100 microg; patients 7-9, 900 microg) with recombinant GM-CSF and IL-2 as adjuvants. IFNgamma ELISPOT showed that naturally processed PSA protein and PSA peptides are recognized by T cells in the blood of some prostate cancer patients after a PSA DNA vaccine. Analysis of other cytokines showed the production of IL-4 and IL-6 but importantly did not show an increase in the number of IL-10-producing cells after vaccination in any of the patients. The authors conclude that a pVAX/PSA DNA vaccine can induce PSA-specific cellular immune responses in patients with hormone-refractory prostate cancer, thus emphasizing the potential for PSA as a target molecule for the immunotherapy of prostate cancer.
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PMID:Immune monitoring in a phase 1 trial of a PSA DNA vaccine in patients with hormone-refractory prostate cancer. 1600 Sep 58

The establishment of metastatic bone lesions in prostate cancer (CaP) is a process partially dependent on angiogenesis. Previously we demonstrated that the stromal-derived factor-1 (SDF-1 or CXCL12)/CXCR4 chemokine axis is critical for CaP cell metastasis. In this investigation, cell lines were established in which CXCR4 expression was knocked down using siRNA technology. When CaP cells were co-transplanted with human vascular endothelial cells into SCID mice, significantly fewer human blood vessels were observed paralleling the reductions in CXCR4 levels. Likewise, the invasive behaviors of the CaP cells were inhibited in vitro. From these functional observations we explored angiogenic and signaling mechanisms generated following SDF-1 binding to CXCR4. Differential activation of the MEK/ERK and PI3K/AKT pathways that result in differential secretion IL-6, IL-8, TIMP-2 and VEGF were seen contingent on the cell type examined; VEGF and TIMP-2 expression in PC3 cells are dependent on AKT activation and ERK activation in LNCaP and LNCaP C4-2B cells leads to IL-6 or IL-8 secretion. At the same time, expression of angiostatin levels were inversely related to CXCR4 levels, and inhibited by SDF-1 stimulation. These data link the SDF-1/CXCR4 pathway to changes in angiogenic cytokines by different signaling mechanisms and, suggest that the delicate equilibrium between proangiogenic and antiangiogenic factors may be achieved by different signal transduction pathways to regulate the angiogenic phenotype of prostate cancers. Taken together, our results provide new information regarding expression of functional CXCR4 receptor-an essential role and potential mechanism of angiogenesis upon SDF-1 stimulation.
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PMID:Diverse signaling pathways through the SDF-1/CXCR4 chemokine axis in prostate cancer cell lines leads to altered patterns of cytokine secretion and angiogenesis. 1600 85

In this study, we have concurrently assayed for IL-2, IL-4, IL-6, IL-10, TNF-alpha, and IFN-gamma in 24-h serum-free cultures of peripheral blood mononuclear cells (PBMC) obtained from seventeen patients with prostate cancer (CaP) per cytokine bead array analysis. The purpose of the study is to examine the nature of the cytokine profile operating among patients and to correlate with their physical, biochemical, and clinical parameters. Unstimulated PBMC cultures from patients with hormone-sensitive metastatic disease demonstrated elevated level of baseline TNF-alpha compared to patients with high-risk, locally advanced disease. Younger patients exhibited significantly higher levels of IL-4 and TNF-alpha compared to older patients following PHA stimulation. Similarly, significantly higher ratios of IFN-gamma/IL-4, IFN-gamma/IL-10, and IL-2/IL-4, a favorable type-1 cytokine pattern, were observed in patients with lower serum PSA compared to patients with high serum PSA. These results indicate the existence of distinct cytokine patterns among patients with CaP.
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PMID:Distinct cytokine patterns exist in peripheral blood mononuclear cell cultures of patients with prostate cancer. 1602 40

We have previously reported that protease-activated receptor 1 (PAR1 or thrombin receptor) is over-expressed in metastatic prostate cancer cell lines compared to prostate epithelial cells. In this study, we examined 1,074 prostate biopsies by tissue microarray analysis and demonstrated that PAR1 expression is significantly increased in prostate cancer compared to normal prostate epithelial cells and benign prostatic hyperplasia. We hypothesized that PAR1 activation contributed to prostate cancer cell progression. We demonstrated that stimulation of PAR1 by thrombin or thrombin receptor activating peptide (TRAP6), in androgen-independent DU145 and PC-3 cells resulted in increased DNA binding activity of the NFkappaB p65 subunit. IL-6 and IL-8 levels were also elevated in conditioned media by at least two-fold within 4-6 h of PAR1 activation. This induction of cytokine production was abrogated by pretreatment of cells with the NFkappaB inhibitor caffeic acid phorbol ester. The p38 and ERK1/2 MAPK signaling cascades were also activated by PAR1 stimulation, whereas the SAPK/JNK pathway was unaffected. Inhibition of p38 and ERK1/2 by SB-203589 and PD-098059, respectively, did not abrogate NFkappaB activity, suggesting an independent induction of NFkappaB by PAR1 stimulation. Furthermore, TUNEL assay showed that activation of PAR1 attenuated docetaxel induced apoptosis through the upregulation of the Bcl-2 family protein Bcl-xL. Akt activation was not observed, suggesting that drug resistance induced by PAR1 was independent of PI3K signaling pathway. Because thrombin and PAR1 are over-expressed in prostate cancer patients, targeting the inhibition of their interaction may attenuate NFkappaB signaling transduction resulting in decreased drug resistance and subsequent survival of prostate cancer cells.
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PMID:PAR1-mediated NFkappaB activation promotes survival of prostate cancer cells through a Bcl-xL-dependent mechanism. 1605 12


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