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)

The apoptosis-inducer Fas and the apoptosis-suppresser Bcl-2 are members of the tumor necrosis factor receptor and Bcl-2 gene superfamilies, respectively. Bcl-2 is overexpressed in hormonally refractory prostate cancer. Fas is expressed in several prostatic carcinoma cell lines but its in vivo expression in normal prostate and in prostate cancer is poorly understood. Formalin-fixed tissue sections from 10 benign prostatic hyperplasias, 10 low-grade and 10 high-grade organ-confined prostate cancers, and 6 metastatic prostate cancers were evaluated for immunoreactivity with Fas and Bcl-2 monoclonal antibodies. In addition, Fas expression was quantitated by computerized cytometry. The results were compared by one-way analysis of variance followed by Bonferroni tests. In benign prostate samples, Bcl-2 and Fas were expressed on basal cells and secretory cells, respectively. Bcl-2 was not expressed in any organ-confined tumors and only in one of six metastatic tumors (17%). Fas was expressed in all organ-confined tumors and in two of six metastatic tumors (33%). Fas expression was significantly decreased (P < 0.001) in prostate cancer (0.20 pg/cell) compared with benign prostate (0.79 pg/cell). The decrease was inversely related to the malignant grade of the tumors (0.30 pg/cell in low-grade tumors, 0.19 pg/cell in high-grade tumors, and 0.003 pg/cell in metastatic tumors). Based on these preliminary data, decreased expression of Fas appears to be an early molecular event in prostate cancer. The decline begins in low-grade tumors. The lowest expression occurs in metastatic carcinomas, which are often Fas negative. Overexpression of Bcl-2 appears to be a later and unrelated molecular event. Both abnormalities may be implicated in tumor progression by prolonging tumor cell survival.
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PMID:Cytometric analysis of Fas and Bcl-2 expression in normal prostatic epithelium and prostate cancer. 1086 56

The low-affinity nerve growth factor receptor p75(NTR) is a 75-kDa glycoprotein that belongs to the tumor necrosis factor receptor superfamily and has been implicated in the induction of apoptosis in various tissues and cell lines. Immunohistochemistry on tissue sections from radical prostatectomies has shown that expression of p75(NTR) is limited to the epithelial cells. Western blot and immunohistochemical analyses have also shown a progressive loss of p75(NTR) expression in prostate epithelial cells during the malignant progression of organ-confined adenocarcinomas, with complete loss of expression in the naturally occurring prostate tumor cell lines DU-145, PC-3, LNCaP, and TSU-pr1, which were derived from metastases. Reintroduction of p75(NTR) expression into the TSU-pr1 tumor cell line was shown to reestablish the ability of these cells to undergo p75(NTR)-mediated apoptosis. It is not known whether this loss of expression is due to deletion of part or the entire p75(NTR) gene or to other factors. Through the use of southern blotting and polymerase chain reaction (PCR), we showed that loss of p75(NTR) protein expression was not due to deletion or loss of the gene. Furthermore, through reverse transcription-PCR, RNase protection, and the chromatin immunoprecipitation assay, we showed that transcription of the p75(NTR) gene occurred in these prostate tumor cell lines. Finally, through transient transfection using two constructs of p75(NTR), one containing the full 2-kb 3' untranslated region and one that contains only a few hundred bases of the 3' untranslated region (UTR), we showed that the 3' UTR may have a role in the loss of p75(NTR) expression in prostate cancer.
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PMID:Molecular characterization of the loss of p75(NTR) expression in human prostate tumor cells. 1139 97

The adaptor protein FADD directly, or indirectly via another adaptor called TRADD, recruits caspase 8 to death receptors of the tumor necrosis factor receptor family. Consequentially, a dominant-negative mutant (FADD-DN, which consists only of the FADD death domain) that binds to receptors but cannot recruit caspase 8 has been widely used to inhibit apoptosis by various stimuli that work via death receptors. Here, we show that FADD-DN also has another cell type- and cancer-dependent activity because it induces apoptosis of normal human prostate epithelial cells but not normal prostate stromal cells or prostate cancer cells. This activity is independent of FADD-DN's ability to bind to three known interacting proteins, Fas, TRADD or RIP suggesting that it is distinct from FADD's functions at activated death receptors. FADD-DN induces caspase activation in normal epithelial cells as demonstrated using a Fluorescence Resonance Energy Transfer assay that measures caspase activity in individual living cells. However, caspase-independent pathways are also implicated in FADD-DN-induced apoptosis because caspase inhibitors were inefficient at preventing prostate cell death. Therefore, the death domain of FADD has a previously unrecognized role in cell survival that is epithelial-specific and defective in cancer cells. This FADD-dependent signaling pathway may be important in prostate carcinogenesis.
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PMID:An apoptosis signaling pathway induced by the death domain of FADD selectively kills normal but not cancerous prostate epithelial cells. 1146 14

Human prostate cancer frequently metastasizes to bone, where it gives rise to osteoblastic bone metastases with an underlying osteoclastic component and subsequent bone pain. However, the importance of osteoclastogenesis in the development of prostate cancer bone lesions in humans is unclear. Osteoprotegerin/osteoclastogenesis inhibitory factor (OCIF) is a member of the tumor necrosis factor receptor family and a novel secreted protein, and it is a negative regulator of osteoclast differentiation, activation, and survival both in vitro and in vivo. In the present study we used a model in which human LNCaP prostate cancer cells that give rise to osteoblastic bone tumors were injected directly into the intramedullary space of human adult bone implanted into nonobese diabetic/severe combined immunodeficient mice to investigate whether the new bone-resorption inhibitor osteoprotegerin/OCIF would inhibit the development of new bone tumors and the progression of established osteoblastic bone tumors. The mice were given consecutive daily s.c. injections of recombinant human OCIF (rhOCIF; 100 micro g/mouse/day) for 2 weeks starting either immediately or 2 weeks after injection of the LNCaP cells. In both protocols, rhOCIF markedly inhibited both the development of bone tumors and the progression of established bone tumor foci quantified by histological examination. Histomorphometrical analysis revealed that rhOCIF markedly reduced the number of osteoclasts and the size of the tumors at the bone sites, but that it had no effect on the local growth of s.c. LNCaP tumors or on LNCaP cell proliferation in culture. These findings demonstrate that osteoclasts play an important role in bone tumor by prostate cancer, and that rhOCIF decreases the LNCaP prostate cancer burden selectively in bone, suppresses the progression of established tumor lesions, and prevents the development of new lesions. These results suggest that inhibition of osteoclastic bone resorption may be an effective therapy for the treatment of prostate cancer that has colonized bone.
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PMID:Osteoprotegerin/osteoclastogenesis inhibitory factor decreases human prostate cancer burden in human adult bone implanted into nonobese diabetic/severe combined immunodeficient mice. 1272 25

Some untranslated sequence (UTR)-localized, short tandem repeats (STRs) exhibit evidence of selection pressure, including STR-coupling preferences, STR conservation, interspecies STR-STR replacements, and STR variants implicated in certain diseases. We wished to determine if STR replacements occurred near disease-related genes, including previously unstudied STRs as well as some STRs already implicated in disease. Among nine strong-candidate prostate cancer (CaP)-predisposing genes, three [steroid 5-alpha-reductase 2 (Srd5A-2), macrophage scavenger receptor-1 (MSR-1), and tumor necrosis factor receptor-21 (Tnfr-21)] exhibited striking STR replacements (P<0.001). The glomerular disease-related gene, CD2AP, exhibited an STR replacement flanked by well-conserved sequences, suggesting an STR-focused process. Another glomerular disease-related gene, rabphilin 3A, exhibited at least two STR replacements at the same UTR position comparing Drosophila melanogaster, Mus musculus, and Homo sapiens. Two genes implicated in blood-clotting disorders, von Willebrand factor (vWA) and fibrinogen alpha (FGA), exhibited multiple-intron STR replacements among mammals, extending STR replacement phenomena to introns. Among primates, a tyrosine hydroxylase (THO1) intron STR, previously implicated in both schizophrenia and drug withdrawal delirium, exhibited frequent replacements. Some STR replacements were early events in gene divergence. When STR sequences of closely related species were available, STR replacement was observed to be nearly as rapid as speciation. STR replacements expand the list of STR sequences that may contribute to genetic activity and to disease processes.
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PMID:Short tandem repeat (STR) replacements in UTRs and introns suggest an important role for certain STRs in gene expression and disease. 1565 86

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

Prostate carcinoma is a hormonally driven age-related neoplasm. Cellular senescence is an age-related process where cells remain metabolically active but in a growth-arrested state at the G1 phase. p14(ARF), p15(INK4b), and p16(INK4a), which are known to regulate G1 cell cycle arrest, and the tumor necrosis factor receptor superfamily member decoy receptor 2 (DCR2), have been recently identified as senescence markers. The purpose of this study was to characterize and compare the expression of p14(ARF), p15(INK4b), p16(INK4a), and DCR2 in tissue microarrays containing cases of normal prostate, nodular hyperplasia, prostate intraepithelial neoplasia (PIN), and malignant prostate cancer tissue. We performed immunohistochemical staining for p14(ARF), p15(INK4b), p16(INK4a), and DCR2 in tissue microarray blocks containing 41 cores of normal prostate, 65 cores of nodular hyperplasia, 21 cores of PIN, 69 cores of low-grade prostate carcinoma, and 42 cores of high-grade prostate carcinoma, derived from 80 cases of prostatectomy with adenocarcinomas. We detected positive staining of p16(INK4a) in 19% of the PIN, 25% of the low-grade carcinoma, and 43% of the high-grade carcinoma specimens but none in the normal prostate and nodular hyperplasia specimens. Expression of p14(ARF) revealed very high levels of expression in normal tissues (83%), nodular hyperplasia (88%), PIN (89%), and cancer cells (100%). P15(INK4b) and DCR2 were found positive in 81 and 33% normal, 46 and 10% nodular hyperplasia, 74 and 36% PIN tissues, 87 and 89% low-grade carcinomas, and 100 and 93% high-grade carcinomas. There is an increased protein expression of senescence-associated molecular markers, indicating that cellular senescence might play a role in prostate carcinoma. Because p16(INK4a)-positive cells were detected only in premalignant lesions and carcinomas but not in normal or benign tissues, p16(INK4a) may aid in the diagnosis of PIN and prostate cancer in difficult cases.
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PMID:Expression of p14ARF, p15INK4b, p16INK4a, and DCR2 increases during prostate cancer progression. 1679 75

By using LNCaP and its derivative cell lines, we first observed an association between tumor necrosis factor-alpha (TNF-alpha) resistance and hormone independence. Moreover, we found that the expression of tumor necrosis factor receptor-associated death domain (TRADD) was reduced in androgen deprivation-independent cells compared with that in androgen deprivation-dependent cells. TRADD is a crucial transducer for TNF-alpha-induced nuclear factor-kappaB (NF-kappaB) activation. Knocking down TRADD expression in LNCaP cells impaired TNF-alpha-induced NF-kappaB activation and androgen receptor repression, whereas overexpression of TRADD in C4-2B cells restored their sensitivity to TNF-alpha. Finally, we found that androgen deprivation reduces TRADD expression in vitro and in vivo, suggesting that androgen deprivation therapy may promote the development of TNF-alpha resistance by reducing TRADD expression during prostate cancer progression.
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PMID:Reduced tumor necrosis factor receptor-associated death domain expression is associated with prostate cancer progression. 1993 28

Molecular chaperones of the heat shock protein-90 (Hsp90) family promote cell survival, but the molecular requirements of this pathway in tumor progression are not understood. Here, we show that a mitochondria-localized Hsp90 chaperone, tumor necrosis factor receptor-associated protein-1 (TRAP-1), is abundantly and ubiquitously expressed in human high-grade prostatic intraepithelial neoplasia, Gleason grades 3 through 5 prostatic adenocarcinomas, and metastatic prostate cancer, but largely undetectable in normal prostate or benign prostatic hyperplasia in vivo. Prostate lesions formed in genetic models of the disease, including the transgenic adenocarcinoma of the mouse prostate and mice carrying prostate-specific deletion of the phosphatase tensin homolog tumor suppressor (Pten(pc-/-)), also exhibit high levels of TRAP-1. Expression of TRAP-1 in nontransformed prostatic epithelial BPH-1 cells inhibited cell death, whereas silencing of TRAP-1 in androgen-independent PC3 or DU145 prostate cancer cells by small interfering RNA enhanced apoptosis. Targeting TRAP-1 with a novel class of mitochondria-directed Hsp90 inhibitors, ie, Gamitrinibs, caused rapid and complete killing of androgen-dependent or -independent prostate cancer, but not BPH-1 cells, whereas reintroduction of TRAP-1 in BPH-1 cells conferred sensitivity to Gamitrinib-induced cell death. These data identify TRAP-1 as a novel mitochondrial survival factor differentially expressed in localized and metastatic prostate cancer compared with normal prostate. Targeting this pathway with Gamitrinibs could be explored as novel molecular therapy in patients with advanced prostate cancer.
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PMID:Cytoprotective mitochondrial chaperone TRAP-1 as a novel molecular target in localized and metastatic prostate cancer. 1994 22

We report that all-trans retinoic acid (ATRA) in combination with zoledronic acid has strong synergistic cytotoxic and apoptotic effects against human hormone- and drug-refractory prostate cancer cells, PC-3 and DU-145, in a time- and dose-dependent manner. We further investigated the effect of the combination treatment on the apoptotic process by both oligoarray and protein array analysis in DU-145 cells, in which the drug combination shows much more strong synergistic effects, as compared to PC-3 cells. Moreover, we have also performed real time-PCR array analysis to validate oligoarray results. We demonstrated that the combination of ATRA and zoledronic acid is a strong inducer of apoptotic related cell death in human androgen-and drug refractory prostate cancer cells DU-145, at either transcriptional or translational levels. While expression of proapoptotic genes such as tumor necrosis factor receptor superfamily (TNFRSF), Bad, Bax, Fas, FADD are induced with the exposure of the combination, expression of antiapoptotic genes or proteins such as members of inhibitor apoptosis family (IAPs), MCL-1, LTBR, p53 and bcl-2 are reduced. Because this novel combination treatment has fewer side effects than is generally the case with conventional cytotoxic agents, this regimen may be a good option for treatment of elderly prostate cancer patients.
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PMID:Regulation of apoptosis-related molecules by synergistic combination of all-trans retinoic acid and zoledronic acid in hormone-refractory prostate cancer cell lines. 2034 82


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