UMLS:C0376358 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Target Concepts:

Query: UMLS:C0376358 (prostate cancer)
59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Most humans in the United States have been infected with BK virus (BKV), a human papovavirus. Because BKV has oncogenic properties, we have investigated whether it may be a cause of human cancer. Basic principles of tumor virology imply that BKV-induced tumors should contain BKV DNA sequences. Therefore, we assayed (by molecular hybridization) DNA from human tumors and malignant cell lines for BKV DNA, using BKV [(32)P]DNA as probe. The BKV [(32)P]DNA was labeled in vitro (nick translation) to specific activities of 1 to 2 x 10(8) cpm/mug. The BKV DNA used to prepare our probes had the properties expected of authentic BKV genomes, including density of superhelical DNA, sedimentation velocity in alkaline and neutral sucrose gradients, production of one fragment by endonuclease EcoRI cleavage and four fragments by endonuclease Hin II + III cleavage and reassociation properties. From these studies we conclude that our BKV probes hybridized well, and represented bona fide BKV DNA. Using three different BKV [(32)P]DNA probes, i.e., from three distinct plaque isolates, we have analyzed DNA from BKV-transformed cells, normal human tissues, and a large number of human tumors. All human DNAs (cell lines, normal tissues, tumors) hybridized 5% with BKV DNA. Hybridization analysis of BKV-transformed hamster cell DNA indicated 5-6 copies of at least 88% of the BKV genome per cell. No BKV DNA sequences were detected (above the normal 5% hybridization to all human DNAs) in the following normal human tissues: 10 kidney (BKV is usually isolated from urine), 3 spleen, 13 lung, 23 colon, 2 rectum, 1 ileum, and 1 skin. No BKV-specific DNA was found in 166 tumors, including 5 carcinomas (Ca) of stomach, 3 Ca small intestine, 26 Ca colon, 9 Ca rectum, 31 Ca lung, 9 adenocarcinomas and 5 oat cell carcinomas of lung, 17 melanomas, 5 Ca prostate, 4 Ca bladder, 6 Wilms tumors, 4 hypernephromas, 15 Ca kidney, 7 brain tumors, 5 Hodgkin lymphomas, 10 lymphomas (immunosuppressed patients have a high incidence of lymphomas), 2 reticulum cell sarcomas (spleen), and 3 skin tumors. We have also analyzed 7 human malignant cell lines (melanoma, lung, rhabdomyosarcoma, and glioblastomas), including several clones of a lung melanoma line; no BKV DNA sequences were detected. Because our probes could detect one copy of BKV DNA if only 10% of the cells were tumor cells, our results are very strong evidence that the tumors we analyzed did not have a BKV etiology. The tumors we tested represent about 50% of all cancers in the United States; there is no evidence that BKV is involved in the etiology of these types of tumors.
...
PMID:Analysis of human tumors and human malignant cell lines for BK virus-specific DNA sequences. 20 40

Androgen-dependent normal prostatic glandular cells and androgen-dependent prostatic cancer cells can be induced to undergo cell death after androgen ablation. This death does not require the cells to proliferate and occurs as an energy-dependent process collectively referred to as "programmed cell death" in which the cells actively commit "suicide." Associated with this programmed cell death pathway is the enhanced expression of a series of genes and the fragmentation of the genomic DNA into nucleosomal oligomers. This genomic DNA fragmentation is the irreversible commitment step in the death of the cell and results from activation of Ca2+/Mg(2+)-dependent endonuclease activity within the cell nucleus. This activation is due to sustained elevation of intracellular free Ca2+ (Cai) induced after androgen ablation. Metastatic prostatic cancer within an individual patient is heterogeneous, including both androgen-dependent and -independent cancer cells. Thus, androgen ablation is rarely curative since it only induces the programmed death of the androgen-dependent cancer cells without activating this pathway in the androgen-independent cancer cells within the patient. Androgen-independent prostatic cancer cells do not activate this death process after androgen ablation, since this does not induce a sustained increase in Cai. A new approach to treat androgen-independent prostatic cancer cells has focused on the use of chemotherapeutic agents to induce a sustained increase in Cai. These studies demonstrate that if such a sustained elevation in Cai is maintained, even androgen-independent prostatic cancer cells undergo programmed cell death.
...
PMID:Androgen regulation of programmed death of normal and malignant prostatic cells. 129 27

Cultured C3 and T5 AXC/SSh rat prostate cancer cells and their conditioned media contained 1000-fold more heparin-binding mitogens than did normal AXC/SSh rat prostates. Immunological analyses confirmed that rat ventral prostate contained only a 17.5 kilodalton (kDa) basic fibroblast growth factor (bFGF)-like mitogen. In contrast, combined immunological and metabolic radiolabeling analyses showed that C3 cells contained 23/24 and 14 kDa bFGF-like polypeptides, whereas the principal bFGF-like polypeptides of C3 cell conditioned medium were proteins having masses of 17.5 and 14 kDa. Identical analyses showed that T5 cells contained 17.5 and 14 kDa bFGF-like polypeptides, whereas the principal bFGF-like polypeptides of T5 cell conditioned medium were proteins having masses of 17.5, 16, and 14 kDa. We found that bFGF-like proteins of mass less than 17.5 kDa, which were present in conditioned medium, were not derived by proteolysis of higher molecular weight bFGF-like mitogens after these were processed into conditioned medium. Northern analyses showed that normal prostate and prostate cancer cells contained acidic fibroblast growth factor transcripts of 6.5 and 3.4 kilobases (kb) and bFGF transcripts of 6.0 and 2.5 kb. Prostate cancer cells also contained a 12-kb bFGF transcript that was not present in normal prostate. Southern analysis of restriction endonuclease-digested normal prostate or prostate cancer cell genomic DNA showed that the 12-kb bFGF transcript was not the product of a rearranged bFGF gene. Our data show that rat prostate cancer cells contain bFGF-like polypeptides of mass 14 to 23/24 kDa and suggest that these cells secrete bFGF-like polypeptides.
...
PMID:Rat prostate cancer cell line-specific production and apparent secretion of heparin-binding growth factors. 138 Dec 14

Androgen ablation induces an energy-dependent process of programmed death in nonproliferating androgen-dependent prostatic cancer cells which involves fragmentation of genomic DNA into nucleosomal oligomers catalyzed by nuclear Ca2+, Mg(2+)-dependent endonuclease enzymes activated following a sustained elevation in intracellular free Ca2+ (Cai). In contrast, androgen-independent prostatic cancer cells are not induced to undergo such programmed cell death by androgen ablation. One explanation for the inability of androgen ablation to induce programmed death of androgen-independent prostatic cancer cells is that such ablation does not result in a sustained elevation in Cai in these cells. This raises the issue of whether androgen-independent prostatic cancer cells can be induced to undergo programmed death if an elevation in the Cai is sufficiently sustained by nonhormonal means. To test this possibility, androgen-independent, highly metastatic Dunning R-3327 AT-3 rat prostatic cancer cells were chronically exposed in vitro to the calcium ionophore ionomycin to sustain an elevation in their Cai. These studies demonstrated that an elevation of Cai as small as only 3-6-fold above baseline can induce the death of these cells if sustained for greater than 12 h. Temporal analysis demonstrated that the death of these cells does not require cell proliferation and involves Ca(2+)-induced fragmentation of genomic DNA into nucleosome-sized pieces as the commitment step in this process. These results demonstrate that even nonproliferating androgen-independent prostatic cancer cells can be induced to undergo programmed cell death if a modest elevation in the Cai is sustained for a sufficient time. These observations identify Cai as a potential target for therapy for androgen-independent prostatic cancer cells.
...
PMID:Programmed death of nonproliferating androgen-independent prostatic cancer cells. 187 14

An androgen receptor (AR) gene mutation identified in the androgen-dependent human prostate cancer xenograft, CWR22, changed codon 874 in the ligand-binding domain (exon H) from CAT for histidine to TAT for tyrosine and abolished a restriction site for the endonuclease SfaNI. SfaNI digestion of AR exon H DNA from normal but not from prostate cancer tissue indicated H874Y is a somatic mutation that occurred before the initial tumor transplant. CWR22, an epithelial cell tumor, expresses a 9.6-kb AR mRNA similar in size to the AR mRNA in human benign prostatic hyperplasia. AR protein is present in cell nuclei by immunostaining as in other androgen-responsive tissues. Transcriptional activity of recombinant H874Y transiently expressed in CV1 cells in the presence of testosterone or dihydrotestosterone was similar to that of wild type AR. With dihydrotestosterone at a near physiological concentration (0.01 nM), H874Y and wild type AR induced 2-fold greater luciferase activity than did the LNCaP mutant AR T877A. The adrenal androgen, dehydroepiandrosterone (10 and 100 nM) with H874Y stimulated a 3- to 8-fold greater response than with wild type AR and at 100 nM the response was similar with the LNCaP mutant. H874Y, like the LNCaP cell mutant, was more responsive to estradiol and progesterone than was wild type AR. The antiandrogen hydroxyflutamide (10 nM) had greater agonist activity (4- to 7-fold) with both mutant ARs than with wild type AR. AR mutations that alter ligand specificity may influence tumor progression subsequent to androgen withdrawal by making the AR more responsive to adrenal androgens or antiandrogens.
...
PMID:Dehydroepiandrosterone activates mutant androgen receptors expressed in the androgen-dependent human prostate cancer xenograft CWR22 and LNCaP cells. 909 97

Androgen receptor (AR) plays a key role in cell growth both in the normal prostate and in prostate cancer. Androgen ablation and prolonged antiandrogen therapy can give rise to AR-dependent prostate tumors, which nonetheless can grow in the androgen-deprived milieu. Here we describe the ribozyme approach to selectively degrading the AR mRNA and thereby inhibiting AR function. A trans-acting hammerhead ribozyme was designed to cleave the rat AR mRNA at the position +1827/ 1828, a region predicted to be minimally involved in generating stable secondary structures. Using AR mRNA fragments as substrates, it was established that this ribozyme can specifically cleave the RNA target in a sequence-specific manner. Kinetic experiments determined a Km for the substrate of 77 nM and a kcat/Km value of 1.8 x 10(7) M(-1) x min(-1), suggesting a catalytic efficiency similar to that of protein enzymes such as the relatively nonspecific ribonuclease A and a sequence-specific endonuclease EcoRI. Transient cotransfections of prostate-derived PC3 cells with three plasmids, an AR-inducible chloramphenicol acetyltransferase (CAT) reporter, an AR expression vector, and a ribozyme expression vector, showed that the ribozyme was capable of reducing the functional activity of AR. At an equimolar ratio of the AR expression plasmid to ribozyme expression plasmid, androgen-inducible CAT activity was inhibited 70%. Similar extents of inhibition were also observed at the cellular mRNA level using ribonuclease protection assays, indicating that the ribozyme functioned as an AR mRNA cleaving enzyme in cellulo. Immunocytochemical examination revealed a decline of AR immunoreactivity in ribozyme-transfected cells. In addition, no morphologically detectable cellular abnormalities were associated with ribozyme expression, indicating the absence of deleterious side effects. These results offer a new avenue for the control of AR function and cell growth, especially in the case of androgen-resistant, but AR-dependent, prostate cancer cells.
...
PMID:Catalytic cleavage of the androgen receptor messenger RNA and functional inhibition of androgen receptor activity by a hammerhead ribozyme. 977 79

Changes in the outer membrane of apoptotic cells can induce neighboring cells to become phagocytic. Using genetically marked prostate cancer cell lines, we explored the possibility that genetic information might be transferred from an apoptotic cell to a phagocytic neighbor. Neomycin-resistant LNCaP cells that overexpress bcl-2 (LNCaP(bcl-2/neo-r)) were cocultured with hygromycin-resistant LNCaP cells (LNCaP(hygr-r)). The cocultures were then transiently exposed to serum starvation to induce apoptosis of LNCaP(hygr-r) cells. Surviving cells were then coselected in medium containing both antibiotics. Whereas monocultures of LNCaP(bcl-2/neo-r) or LNCaP(hygr-r) treated this way yielded no colonies, cocultures yielded dual-antibiotic-resistant clones at a frequency of approximately 1 in 10(5). Pre-exposure to an apoptotic agent was required; cocultures not exposed to serum starvation yielded no dual-selectable colonies. Analysis of DNA extracted from a dual-resistant clone demonstrated that the restriction endonuclease pattern of the neo-r gene was unaltered when compared with the parental LNCaP(bcl-2/neo-r). However the hygr-r gene demonstrated an altered restriction endonuclease pattern in the dual-resistant derivative compared with the parental LNCaP(hygr-r) cell line. This is evidence that genetic information can be transferred from one prostate cancer cell to another through the process of apoptosis, and we term this form of genetic transfer "apoptotic conversion."
...
PMID:Apoptotic conversion: evidence for exchange of genetic information between prostate cancer cells mediated by apoptosis. 1055 18

Neutral endopeptidase 24.11 (NEP) is a cell surface peptidase expressed by prostatic epithelial cells that cleaves and inactivates neuropeptide growth factors implicated in the growth of androgen-independent prostate cancer (PC). Decreased NEP expression in hormone-refractory metastatic PCs can result from hormonal therapies because NEP transcription is induced by androgens and down-regulated by androgen withdrawal. NEP is encoded by a gene that contains a 5' CpG island spanning a transcriptional regulatory region. In this study, we investigate whether DNA hypermethylation of the NEP promoter accompanies decreased NEP expression in PC cell lines and whether it occurs in human PC tissues in vivo. DNA isolated from PC cell lines and from normal and neoplastic human prostate tissues was restriction-digested with a methylation-sensitive restriction endonuclease and analyzed by Southern blot using a 5' sequence-specific NEP probe. Methylation-specific PCR was performed using PCR primers designed to discriminate between methylated and unmethylated alleles, and reverse transcription-PCR using NEP-specific primers was performed on cDNA extracted from PC cells treated with 5-aza-2'-deoxycytidine. Methylation of the NEP promoter was present in androgen-independent PC cell lines but not in androgen-dependent or small-cell derived PC cell lines and in 3 of 21 (14%) primary PCs from patients with androgen-dependent disease. Exposure of PC cells to the demethylating agent 5-aza-2'-deoxycytidine led to an increase in NEP transcripts in DU-145 and PC-3 cells. These data show that hypermethylation of the 5' CpG NEP island is associated with a loss of NEP expression in PC. Loss of NEP expression via hypermethylation of the NEP promoter may contribute to the development of neuropeptide-stimulated PCs.
...
PMID:Methylation of the neutral endopeptidase gene promoter in human prostate cancers. 1081 84

New diagnostic tools are needed for the early detection of prostatic cancer. The molecular detection of prostate cancer cells in ejaculates was evaluated using complementary PCR-based methods. LNCaP cells, a cell line derived from prostatic carcinoma, were spiked into normal seminal ejaculates and the prostatic epithelial component of the specimens was isolated by immunomagnetic bead sorting, using a monoclonal antibody to prostate-specific membrane antigen (PSMA). Ejaculates from nine patients with a recent diagnosis of prostate cancer were processed in a similar fashion, using LNCaP-spiked aliquots as an internal positive control. Telomerase expression was evaluated by the telomeric repeat amplification protocol (TRAP) and glutathione S-transferase gene promoter (GSTP1) hypermethylation was evaluated by methylation-sensitive restriction endonuclease digestion and PCR amplification. Telomerase activity was detected in LNCaP cells recovered from normal seminal ejaculates but was not found in all nine samples from patients with prostate cancer. The sensitivity of GSTP1 analysis was similar to telomerase analysis for the detection of LNCaP cells from normal ejaculate samples but was positive in ejaculates from four out of nine patients with prostate cancer. GSTP1 DNA methylation status is more sensitive than telomerase analysis for the detection of malignant cells in seminal ejaculates from patients with prostate cancer.
...
PMID:Comparison of telomerase activity and GSTP1 promoter methylation in ejaculate as potential screening tests for prostate cancer. 1097 Jul 25

The DNA base excision repair pathway is responsible for the repair of cellular alkylation and oxidative DNA damage. A crucial step in the BER pathway involves the cleavage of baseless sites in DNA by an apurinic/apyrimidinic or baseless (AP) endonuclease (Ape1/ref-1), which is a multifunctional enzyme that acts not only as an AP endonuclease but also as a redox-modifying factor for a variety of transcription factors including Fos, Jun, paired box containing genes (PAX), nuclear factor-kappaB, hypoxia-inducible factor alpha (HIF-1alpha), HIF-like factor (HLF), p53, and others. The expression of Ape1/ref-1 in prostate has not been characterized previously. Ape1/ref-1 nuclear immunohistochemistry levels, scored for intensity as 1+, 2+, or 3+, were 91, 3, and 6% in benign hypertrophy (BPH), 0, 42, and 58% in prostatic intraepithelial neoplasia (PIN) and 3, 30, and 67% in prostate cancer, respectively, clearly showing an increase in Ape1/ref-1 nuclear staining in the PIN and cancer compared with BPH. Furthermore, the level of cytoplasmic staining of Ape1/ref-1 in cancer and PIN were elevated (42 and 36%, respectively) compared with BPH (5%). There was no correlation with prostate-specific antigen values or doubling times to Ape1/ref-1 levels. In conclusion, we have demonstrated that Ape1/ref-1 is dramatically elevated in prostate cancer, the level of staining of Ape1/ref-1 increases from low in BPH to intense in PIN and cancer, and there is an increase in the amount of Ape1/ref-1 in the cytoplasm of PIN and cancer compared with BPH. Given these results, we conclude that Ape1/ref-1 may be a diagnostic marker for early prostate cancer and play a role, through its repair, redox, or both functions, in the physiology of the early development of prostate cancer.
...
PMID:Elevated and altered expression of the multifunctional DNA base excision repair and redox enzyme Ape1/ref-1 in prostate cancer. 1130 29

1 2 Next >>