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)

Prostate cancer is the most commonly diagnosed form of malignant neoplasia in men. Considerable evidence has accumulated suggesting that paracrine interactions between stromal cells and epithelial cells mediate, in part, the growth and development of the prostate. A nerve growth factor-like protein secreted by stromal cells has been implicated in the paracrine regulation of prostate epithelial tumor cell growth in vitro. This prostate-derived nerve growth factor-like protein differs from the known members of the neurotrophin family of proteins, and may represent a prostate-specific form of this family of gene products. Furthermore, corresponding nerve growth factor receptors have been localized to the epithelial cells of the human prostate in vivo, consistent with a role of the receptors and the adjacent nerve growth factor-like protein secreted by stromal cells, in the paracrine regulation of prostate growth and neoplasia.
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PMID:Role of nerve growth factor-like protein in the paracrine regulation of prostate growth. 129 29

Members of the K252 family of kinase inhibitors have been demonstrated to inhibit a number of neurotrophin-mediated cellular responses, and to preferentially inhibit the activity of neurotrophin receptors. In this study, we examined the effects of K252a and K252b on the growth of human prostate carcinoma cells, whose growth is, in part, mediated by a prostatic nerve growth factor(NGF)-like protein(s). K252a inhibited [3H]thymidine incorporation by three androgen-independent prostate tumor cell lines (TSU-pr1, DU-145, and PC-3), under basal growth conditions, and in response to growth stimulation by human prostatic stromal (hPS) cell proteins and serum. K252b, which does not readily penetrate cell membranes, had no significant effect on [3H]thymidine incorporation by the prostate tumor cell lines. The decrease in [3H]thymidine incorporation by the cell lines in response to K252a did not appear to be the result of K252a cytotoxicity at concentrations as high as 100 nM, as measured by the Trypan blue assay for cell viability. Treatment of cells for 25 hours with 100 nM K252a resulted in accumulation of TSU-pr1, DU-145, and PC-3 cells in G0/G1, concurrent with a substantial decrease in cells synthesizing DNA. Treatment of androgen-responsive LNCaP prostatic carcinoma cells for 25 hours with 100 nM K252a also resulted in a significant decrease in DNA synthesis. Human recombinant NGF-mediated phosphorylation of a 140-kDa Trk NGF receptor in the TSU-pr1 cell line was inhibited by treatment with 100 nM K252a. Hence, K252a inhibition of Trk phosphorylation most probably contributed, in part, to the inhibition of prostate tumor cell growth in vitro. These results suggest that the mechanism of K252a action may be useful in the design of potential therapies for prostate cancer treatment.
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PMID:Anti-proliferative effect of the kinase inhibitor K252a on human prostatic carcinoma cell lines. 895 91

The indolocarbazole analogue CEP-751 is a potent and selective tyrosine kinase inhibitor of the neurotrophin-specific trk receptors that has demonstrated antitumor activity in nine different models of prostate cancer growth in vivo. In the slow-growing, androgen-sensitive Dunning H prostate cancers, which express trk receptors, CEP-751 induced transient regressions independent of effects on cell cycle. Because androgen ablation is the most commonly used treatment for prostate cancer, we examined whether the combination treatment of CEP-751 with castration would lead to better antitumor efficacy than either treatment alone. For a 60-day period, H tumor-bearing rats received treatment with either castration, CEP-751 (10 mg/kg once a day s.c. for 5 days every 2 weeks), a combination of both, or vehicle. Castration caused tumor regression, followed by tumor regrowth in 4-6 weeks, whereas intermittent CEP-751 treatments resulted in tumor regressions during each treatment, which were followed by a period of regrowth between intermittent drug treatment cycles. Overall, both monotherapies significantly inhibited tumor growth compared with the vehicle-treated control group. However, the combination of castration and concomitant CEP-751 produced the most dramatic results: sigificantly greater tumor regression than either therapy alone, with no signs of regrowth. A related experiment using an orally administered CEP-751 analogue (CEP-701), as the trk inhibitor, and a gonadotrophin-releasing hormone agonist, Leuprolide, to induce androgen ablation demonstrated similar results, indicating that these effects could be generalized to other forms of androgen ablation and other trk inhibitors within this class. In addition, when CEP-701 was given sequentially to rats bearing H tumors, which were progressing in the presence of continuous androgen ablation induced by Leuprolide, regression of the androgen-independent tumors occurred. In summary, these data demonstrate that CEP-751 or CEP-701, when combined with surgically or chemically induced androgen ablation, offer better antitumor efficacy than either monotherapy and suggest that each therapy produces prostate cancer cell death through complementary mechanisms.
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PMID:Sustained in vivo regression of Dunning H rat prostate cancers treated with combinations of androgen ablation and Trk tyrosine kinase inhibitors, CEP-751 (KT-6587) or CEP-701 (KT-5555). 1034 49

Nerve growth factor (NGF) is expressed in the prostate, where it appears to be involved in the control of epithelial cell growth and differentiation. NGF production is decreased in prostate tumors. However, the role of this neurotrophin in the control of proliferation and progression of prostate cancers is still a matter of investigation. Prostate adenocarcinomas are telomerase-positive tumors. Chronic exposure of DU145 and PC3 prostate tumor cell lines to NGF resulted in a dramatic down-regulation of telomerase activity. This effect was correlated in terms of concentrations and time with a remarkable down-regulation of cell proliferation both in vitro and in vivo but was not secondary to NGF-induced quiescence. No down-regulation of telomerase activity was, in fact, detectable during serum starvation-induced quiescence. LNCaP cells, which do not express NGF receptors, appear to be insensitive to the actions of NGF. DU145 and PC3 cells do not express the KAI1 metastasis suppressor gene, which is present in the prostate and is progressively lost during the progression of prostate cancers. Chronic NGF treatment strongly induced the reexpression of this gene in these cell lines, and this effect was correlated with the suppression of their invasive potential in vitro. The data presented here suggest that NGF reverts two metastatic prostate cancer cell lines to slowly proliferating, noninvasive phenotypes characterized by a very low telomerase activity and by the expression of the KAI1 metastasis suppressor gene.
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PMID:Suppression of telomerase, reexpression of KAI1, and abrogation of tumorigenicity by nerve growth factor in prostate cancer cell lines. 1035 59

During development, neurons pass through a critical phase in which survival is dependent on neurotrophin support. In order to dissect the potential role of p75NTR, the common neurotrophin receptor, in neurotrophin dependence, we expressed wild-type and mutant p75NTR in cells that do not express endogenous p75NTR or Trk family members (NIH3T3). Expression of wild-type p75NTR created a state of neurotrophin dependence: cells could be rescued by nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), or neurotrophin-3 (NT-3), but not by a mutant NGF that binds well to Trk A but poorly to p75NTR. Similarly, expression of p75NTR in human prostate cancer cells in culture rendered a metastatic tumor cell line (PC-3) sensitive to the availability of neurotrophins for survival. Moreover, expression of mutant p75NTR's in another neurotrophin-insensitive cell line (HEK293T) showed that a domain within the intracellular domain governs alternate responses to neurotrophins: the carboxy terminus of the intracellular domain of p75NTR including the sixth alpha helix domain is necessary for rescue by BDNF, but not NGF. These results, when considered with previous studies of the timing of p75NTR expression, support the hypothesis that p75NTR is a mediator of neurotrophin dependence during the critical phase of developmental cell death and during the progression of carcinogenesis in prostate cancer.
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PMID:Neurotrophin dependence mediated by p75NTR: contrast between rescue by BDNF and NGF. 1063 39

Prostate cancer frequently metastasizes to the skeleton, producing painful osteoblastic lesions, which are associated with significant morbidity and mortality. This bone tropism involves the bidirectional paracrine interactions between prostate cancer cells and osteoblasts. These interactions enhance prostate cancer cell survival and proliferation of osteoblasts. Therefore, agents that can induce apoptosis of prostate cancer cells and proliferating osteoblasts would be highly advantageous. Previously, we have documented that the unique survival pathway for prostate cancer cells involves a neurotrophin/Trk receptor autocrine pathway. The indocarbazole compounds, CEP-701 and CEP-751, are potent inhibitor of this Trk receptor survival signaling and thus selectively induces apoptosis of prostate cancer cells in various in vitro and in vivo models. In this study, we documented the effects of CEP-751 on the conditionally immortalized osteoblastic cell line, hFOB, in vitro. At the permissive temperature of 34 degrees C, these cells express large T antigen, inducing their continuous proliferation, whereas at 39 degrees C, T antigen is degraded and the cells stop proliferating without undergoing apoptosis. Trk receptors are expressed in hFOB cells, as determined both by reverse transcription-PCR and Western blots. These osteoblasts were shown to produce nerve growth factor and brain-derived neurotrophic factor but not neurotrophin-3, as measured by ELISA. hFOB osteoblasts, cultured at 34 degrees C, secreted significantly (P < 0.01) more brain-derived neurotrophic factor and nerve growth factor into the medium than hFOB cells cultured at 39 degrees C. Because the Trk/neurotrophin axis is present in both proliferating and quiescent (i.e., nonproliferating) osteoblasts, the effects of 48 h of exposure to various doses of CEP-751 on cell viability and apoptosis of hFOB cells were assessed by trypan blue exclusion assays and 4',6-diamidino-2-phenylindole nuclear staining. Cell viability and apoptosis of hFOB cells at 34 degrees C were significantly and dose-dependently decreased compared with untreated proliferating cells. In contrast, even the highest concentration of CEP-751 (200 nM) did not affect cell viability and apoptosis of quiescent hFOB cells cultured at 39 degrees C. This trk inhibition-induced cytotoxicity was confirmed using early-passage, proliferating normal (i.e., non-SV40-transformed) human osteoblasts, which also express Trk receptor protein. These combined results demonstrate that proliferating osteoblasts acquire a sensitivity to trk inhibition- induced apoptosis not shared with normally quiescent osteoblasts.
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PMID:Trk receptor inhibition induces apoptosis of proliferating but not quiescent human osteoblasts. 1186 69

Epigenetic change such as DNA methylation is one important mechanism for regulating gene expression as genetic change, such as mutation or loss of heterozygosity. Methylation of cancer-related genes has been shown to play an important role in carcinogenesis and tumor progression. Using methylated CpG island amplification (MCA)/representational difference analysis (RDA), we identified four CpG islands in neurotrophin tyrosine kinase receptor type 2 (NTRK2), Protocadherine Flamingo1 and MFPC (Methylated Fragments in Prostate Cancer) 7 and 8. Bisulfite sequencing revealed that 2 regions of NTRK2 as well as MFPC7 and MFPC8 were aberrantly methylated in prostate cancer cell lines, and COBRA showed that 48 (76.24%), 37 (58.7%) and 14 (22.2%) of 63 prostate cancer tissues were methylated, respectively, for these sites. On the other hand, none of 13 benign prostate samples were methylated, except for 1 (7.7%) with NTRK2. For NTRK2, mRNA expression was negative in prostate cancer cell lines (LNCaP and DU145) but was recovered on a methyltransferase inhibitor (5-Aza-CdR) treatment. The role of NTRK2 within NTRK remains unclear. Our results suggest that these 3 hypermethylated DNA fragments also may be markers of prostate cancer detection.
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PMID:Identification of differentially methylated CpG islands in prostate cancer. 1538 91

The expression of the p75 neurotrophin receptor (p75NTR) is diminished in epithelial cells during progression of prostate cancer in vivo and in vitro. Previous studies have demonstrated a role for p75NTR as a tumor suppressor in prostate growth. To better understand the molecular mechanism of p75(NTR) on tumor suppression, we utilized a complementary deoxyribonucleic acid microarray composed of approximately 6,000 human cancer-related genes to determine the gene expression pattern altered by re-introduction of p75NTR into PC-3 prostate tumor cells. Comparison of the transcripts in the neo and p75NTR-transfected cells revealed 52 differentially expressed genes, of which 21 were up-regulated and 31 were down-regulated in the presence of p75NTR. Based on the known biological functions of the p75NTR-regulated genes, we observed that p75NTR modulated the expression of genes that are critically involved in the regulation of differentiation as well as cell adhesion, signal transduction, apoptosis, tumor cell invasion, and metastasis. Several differentially expressed genes identified by microarray were selected for confirmation using quantitative real-time polymerase chain reaction. Immunoblot analysis further confirmed increased cellular retinoic acid-binding protein I (CRABPI) and IGFBP5 protein levels and decreased level of PLAUR protein with increasing p75NTR protein expression. As CRABPI was elevated far more than any other genes, we observed that the retinoids, all-trans retinoic acid and 9-cis retinoic acid, that bind CRABPI, promoted nitroblue tetrazolium-associated functional cell differentiation in p75NTR PC-3 cells, but not in neo control PC-3 cells. Subsequent examination of the retinoic acid receptors (RARs) expression levels demonstrated an absence of RAR-beta in the neo control cells and re-expression in the p75NTR expressing cells, consistent with previous findings where RAR-beta is believed to play a critical role as a tumor suppressor gene that is lost during de-differentiation of prostate epithelial cells. Whereas the RAR-alpha and -gamma protein levels remained unchanged, retinoid X receptor (RXR)-alpha and -beta also exhibited increasing protein levels with re-expression of the p75NTR protein. Moreover, the ability of p75NTR siRNA to knockdown levels of RAR-beta, RXR-alpha, and RXR-beta supports the specificity of the functional involvement of p75NTR in differentiation. Hence, re-expression of the p75NTR appears to partially reverse de-differentiation of prostate cancer cells by up-regulating the expression of CRABPI for localized sequestration of retinoids that are available to newly up-regulated RAR-beta, RXR-alpha, and RXR-beta.
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PMID:A novel function of differentiation revealed by cDNA microarray profiling of p75NTR-regulated gene expression. 1631 9

The p75 neurotrophin receptor (p75(NTR)) is a death receptor which belongs to the tumor necrosis factor receptor super-family of membrane proteins. This study shows that p75(NTR) retarded cell cycle progression by induced accumulation of cells in G0/G1 and a reduction in the S phase of the cell cycle. The rescue of tumor cells from cell cycle progression by a death domain deleted (DeltaDD) dominant-negative antagonist of p75(NTR) showed that the death domain transduced anti-proliferative activity in a ligand-independent manner. Conversely, addition of NGF ligand rescued retardation of cell cycle progression with commensurate changes in components of the cyclin/cdk holoenzyme complex. In the absence of ligand, p75(NTR)-dependent cell cycle arrest facilitated an increase in apoptotic nuclear fragmentation of the prostate cancer cells. Apoptosis of p75(NTR) expressing cells occurred via the intrinsic mitochondrial pathway leading to a sequential caspase-9 and -7 cascade. Since the death domain deleted dominant-negative antagonist of p75(NTR) rescued intrinsic caspase associated apoptosis in PC-3 cells, this shows p75(NTR) was integral to ligand independent induction of apoptosis. Moreover, the ability of ligand to ameliorate the p75(NTR)-dependent intrinsic apoptotic cascade indicates that NGF functioned as a survival factor for p75(NTR) expressing prostate cancer cells.
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PMID:The p75(NTR) tumor suppressor induces cell cycle arrest facilitating caspase mediated apoptosis in prostate tumor cells. 1646 Jun 73

The p75 neurotrophin receptor (p75(NTR)) has been characterized as a metastasis and tumor suppressor in prostate cancer. In order to investigate the mechanism(s) by which the p75(NTR) functions as a metastasis suppressor in prostate cancer cells, we characterized the ectopic expression of p75(NTR) on the urokinase plasminogen activator (uPA) and the type IV collagen matrix metalloproteinases (MMP-2 and MMP-9) in PC-3 human prostate cancer cells. Rank-order expression of p75(NTR) greatly reduced protein levels and enzymatic activities of uPA, MMP-2, and MMP-9 as shown by immunoblot and zymography analyses. Conversely, expression of the MMP-9 antagonist, tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) exhibited an increase in protein levels with an increase in p75(NTR) levels, whereas TIMP-2 was not detected. Transient transfection with an inducible dominant negative antagonist Deltap75(NTR) rescued uPA, MMP-2, and MMP-9 protein levels and protease activities, and conversely suppressed TIMP-1 levels. Since p75(NTR) signal transduction occurs via the NFkappaB and JNK pathways, antagonism of signaling intermediates in these pathways, using dominant negative IKKbeta or dominant negative MKK-4, respectively, was shown to further decrease expression of uPA, MMP-2, and MMP-9 protein and enzymatic activity levels, and conversely up-regulate levels of TIMP-1. These results indicate that expression of uPA, MMP-2, MMP-9, and TIMP-1 are directly regulated by expression of p75(NTR) and its downstream signal transduction cascade. These results suggest that the metastasis suppressor activity of p75(NTR) is mediated, in part, by down-regulation of specific proteases (uPA, type IV collagenases) implicated in cell migration and metastasis.
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PMID:The p75(NTR) metastasis suppressor inhibits urokinase plasminogen activator, matrix metalloproteinase-2 and matrix metalloproteinase-9 in PC-3 prostate cancer cells. 1691 16


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