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)

12-O-tetradecanoyl phorbol ester (TPA) has profound cytotoxic effects on a human prostate cancer cell line, LNCaP. The TPA effect may be mediated via a protein kinase C (PKC) pathway, since staurosporine, a potent PKC inhibitor, could reverse the cell-killing effect. Our studies, based on cellular fragmentation, chromatin condensation, and nuclear fragmentation, suggest that the cell-killing effect is due to apoptosis. Moreover, we also examined expression of early growth response genes and androgen-induced genes in association with TPA-induced apoptosis. Northern blot analysis demonstrated that androgen induction of human glandular kallikrein-1 (hKLK2) mRNA was repressed by TPA in a concentration-dependent manner. A time course study showed that both hKLK2 and c-myc mRNAs were repressed by TPA as early as four hours. In contrast, the steady state mRNA levels for c-fos, c-jun, nerve growth factor induced gene A, and the orphan steroid receptor nur77 were rapidly induced within the first two hours of the treatment. Furthermore, transient co-transfection experiments demonstrated that c-fos and c-jun could repress androgen receptor-mediated gene induction. The above studies suggest that (1) the repression of androgen induction of gene expression by TPA-activated PKC is at least in part due to overexpression of c-jun and c-fos and (2) PKC may be a negative growth regulator in prostate cells.
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PMID:Tumor-promoting phorbol ester-induced cell death and gene expression in a human prostate adenocarcinoma cell line. 784 43

The proliferation of the human prostatic cancer JCA-1 cells showed a complex response to different concentrations of TPA. Whereas cells exposed for 24 h had growth reduction which was proportional to the concentration of TPA added to the culture media, they showed resistance to low (0.016 and 0.16 nM) but not high (> or = 1.6 nM) doses of TPA after 72 h. Growth-inhibited, treated cells also displayed a distinct cell morphology compared with the controls. Since c-myc expression has previously been shown to be correlated with cellular proliferation, we determined changes in its steady-state level in control and treated cells by Northern analysis. Following a 24h, 48h, and 72h treatment, with 16 nM TPA, c-myc mRNA was suppressed by 91%, 83%, and 78%, respectively, in good agreement with the extent of growth reduction observed. At the low dose of TPA (0.16 nM), however, the c-myc mRNA expression remained inhibited by 85% even though cell growth was only reduced by 10-14%. No difference in the total amount of c-myc protein could be detected between control and treated cells by Western analysis.
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PMID:Regulation of cell growth and the c-myc proto-oncogene expression by phorbol ester 12-0-tetradecanoyl phorbol-13-acetate (TPA) in the androgen-independent human prostatic JCA-1 cells. 784 24

Androgen-independent Dunning R-3327 AT-3 rat prostatic cancer cells can be induced to undergo programmed cell death in either a proliferation-dependent or independent manner depending upon the therapeutic agent used. In the present study, 5-fluorodeoxyuridine (5-FrdU) was used to induce proliferation-dependent death of the AT-3 cells via its ability to inhibit thymidylate synthetase. Ionomycin and thapsigargin were used to induce proliferation-independent death of these cells via their ability to sustain an elevation in intracellular free Ca2+. Based upon the temporal sequence of DNA fragmentation, morphologic changes, and loss of cell viability, each of the three test agents, at the doses used, induces the programmed death of AT-3 cells with essentially identical kinetics. Based upon these similarities, comparisons of the pattern of gene expression during the proliferation-dependent (i.e., 5-FrdU-induced) vs. proliferation-independent (i.e., ionomycin and thapsigargin-induced) programmed death of AT-3 cells allow identification of genes whose enhanced expression is involved in the initiation vs. completion of programmed cell death. Based upon this approach, enhanced H-ras and TRPM-2 expression is associated with initiation of proliferation-dependent programmed death of AT-3 cells while enhanced c-myc, calmodulin, and alpha-prothymosin expression is associated with initiation of proliferation-independent programmed death of these cells. In contrast, enhanced expression of glucose-regulated 78 kilodalton and tissue transglutaminase genes are associated with the completion of programmed cell death, since their expression is enhanced in both proliferation-dependent and independent programmed cell death of AT-3 cells.
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PMID:Proliferation-dependent vs. independent programmed cell death of prostatic cancer cells involves distinct gene regulation. 799 34

Previous studies have demonstrated that androgen responsive human prostate cancer cells can be induced to undergo programmed cell death after androgen ablation. By contrast, androgen-independent human prostate cancer cells do not activate this apoptotic pathway in response to androgen ablation. In the present study, two androgen-independent human prostatic cell lines, PC-3 and DU-145, were used as in vitro model systems to investigate the possibility of induction of programmed cell death in response to non-androgen ablative cytotoxic drugs. Treatment of these cells with the fluorinated pyrimidines, 5-fluoro-2-deoxyuridine or trifluorothymidine, resulted in a significant decrease in cell viability, over a period of 96 hr of exposure to the drugs, as determined by the trypan blue exclusion assay. The characteristic DNA fragmentation into a nucleosomal ladder and induction of expression of specific apoptosis-related genes, such as TRPM-2/SGP-2, and TGF-beta 1, but not the growth-related genes, c-myc, c-fos, and p53, temporally correlated with activation of apoptotic cell death in both systems. Simultaneous treatment with exogenous thymidine completely abrogated the fluoropyrimidine-induced cytotoxic effect in both cell lines, as well as the nucleosomal fragmentation of DNA, indicating that this apoptotic process is due to the induction of "thymineless" state. These results suggest that androgen-independent human prostate cancer cells retain the ability to activate the apoptotic cascade, after treatment with cytotoxic drugs that induce a "thymineless" state.
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PMID:Induction of apoptosis in androgen-independent human prostate cancer cells undergoing thymineless death. 803 80

The progression of prostatic adenocarcinoma from localized disease to metastatic carcinoma appears to be a multi-step sequence. The expression of common oncogenes/oncosuppressor genes and the mediating effect of neuroendocrine tumor cells may play a role in this progression. The expression of the more frequently investigated oncogenes/oncosuppressor genes (p53, c-myc, c-erbB-2, bcl-2) and the presence of neuroendocrine cells were assessed in prostatic cancer tissue from patients with localized and metastatic cancer. These oncogenes/oncosuppressor genes were evaluated according to tumor stage and grade and their relationship to one another. Grade was not related to any of the oncogene markers or to the presence of neuroendocrine cells. Advancing stage was associated with a significant increase in p53 expression, while other markers remained constant in all stages. Neuroendocrine cells, p53, c-myc, c-erbB-2 and bcl-2 were rarely co-expressed at any stage of prostate cancer.
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PMID:Immunohistochemical detection of oncogene proteins and neuroendocrine differentiation in different stages of prostate cancer. 853 88

The DNA sequence of the genes for the androgen receptor (AR) and TATA-binding protein (TBP), like many other genes encoding transcription factors, contains a series of tandem CAG repeats. Here we explore the capacity of complementary peptide nucleic acids (PNAs) to invade the CAG triplets of the AR and TBP genes in human prostatic cancer cells and show that the PNAs readily entered the nuclei of lysolecithin-permeabilized cells and effectively inhibited sense transcription of unique AR and TBP DNA sequences downstream of the site of PNA.DNA hybridization, but not upstream of that site. These PNAs had little or no effect on transcription of the c-myc gene, which lacks a CAG triplet domain. Conversely, a PNA complementary to a unique sequence of the c-myc gene did not inhibit transcription of the AR or TBP genes but did inhibit c-myc transcription. Comparisons of PNA effects on sense and antisense transcription of the AR, TBP, and c-myc genes confirm that progression of the RNA polymerase complex beyond the site of PNA.DNA hybridization is impaired in both directions. Suppression of the AR gene results in refolding of a transcriptionally active nucleosome containing a unique 17-mer AR DNA sequence.
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PMID:Invasion of the CAG triplet repeats by a complementary peptide nucleic acid inhibits transcription of the androgen receptor and TATA-binding protein genes and correlates with refolding of an active nucleosome containing a unique AR gene sequence. 866 37

There are three nearly ubiquitous genomic "imbalances" in prostate cancer cells: 1) loss of sequences from the short arm of chromosomes 8, 2) loss of sequences from the long arm of chromosome 13q, and 3) gain of sequences on the long arm of chromosome 8, particularly in advanced disease. Candidate tumor suppressor genes and oncogenes affected by this trio of consistent changes include the c-myc gene on chromosome 8q24, the RB gene at 13q14, and potentially multiple novel genes on the short arm of chromosome 8, with a gene located more proximally potentially involved in tumor initiation and a gene or genes located more distally involved in tumor progression. Loss of regions of chromosomes 2q, 5q, 6q, 7p and 7q, 9p, 10p and 10q, 16q, 17p and 17q, and 18q, and gain of regions of 1q, 2p, 3p and 3q, 7p and 7q, 11p, 17q, and Xq have also been detected in the range of 25-50% of tumors studied. Analysis of candidate tumor suppressor genes in these regions is still in its early stages. Similarly, potential oncogenes on a series of chromosomal arms which undergo frequent amplification remain essentially uncharacterized. The basic outline of the chromosomal aberrations in prostate cancer has been well established; the details of the story remain to be filled in. This paper reviews the advantages and disadvantages of various techniques for detection of genomic loss and gain in prostate cancer cells, and reviews published reports of loss and gain in prostate cancer, focusing primarily on reports using microsatellite analysis, Southern analysis, and comparative genomic hybridization. Fluorescence in situ hybridization (FISH) based analyses of selected regions are also reviewed.
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PMID:Review of allelic loss and gain in prostate cancer. 891 74

Growth arrest and differentiation of leukemic cells by phorbol 12-myristate 13-acetate (PMA) is accompanied by p53-independent activation of p21WAF1/CIP1 and c-myc down-regulation. We show that despite p21 induction in 7 of 12 human cancer cell lines treated with PMA, growth inhibition was observed only in two cell lines (SKBr3 breast and LNCaP prostate cancer cells). Treatment of SKBr3 and LNCaP cells with PMA was followed by Raf-1 hyperphosphorylation, p21 induction, Rb hypophosphorylation, c-myc down-regulation and growth inhibition. The 10 remaining PMA-resistant cell lines were comprised of 5 that failed to induce p21 and 5 that induced p21 but had defects in steps putatively downstream of this (Rb hypophosphorylation and c-myc down-regulation). Exogenous expression and subsequent failure to down-regulate c-myc protein expression in SKBr3 and LNCaP cells was correlated with acquisition of resistance to the growth inhibitory effect of PMA. Exogenous p21 expression down-regulated c-myc protein in PMA-sensitive cancer cells. Our findings suggest that induction of p21 and down-regulation of c-myc may be necessary steps in a PMA-induced growth-inhibitory pathway in cancer cells.
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PMID:Defects in p21WAF1/CIP1, Rb, and c-myc signaling in phorbol ester-resistant cancer cells. 900 May 76

Previous studies have demonstrated that overexpression of urinary plasminogen activator (uPA) in rat prostate cancer cells results in increased skeletal metastases, which are primarily of the osteoblastic variety. The osseous activation induced by the metastases appears to be mediated through the amino terminal fragment (ATF) of uPA, which lacks the catalytic domain and can act as a growth factor for osteoblasts. To explore further the mechanism of action of uPA in bone cells, we evaluated the effects of ATF on modulating the expression of various proto-oncogenes. Human-osteoblast-derived osteosarcoma cells, SaOS2, were treated with graded doses of ATF for 10-120 min, and effects on early response proto-oncogenes were monitored. ATF increased c-myc, c-jun, and c-fos gene expression in a time-dependent manner for up to 60 min, after which mRNA levels fell. The maximum induction was seen in c-fos gene expression, which was found to be dose dependent. This effect of ATF was localized to its growth-factorlike domain. Examination of the half life of these transcripts in the presence of the transcriptional inhibitor actinomycin D demonstrated that ATF does not alter the stability of c-fos mRNA in these bone cells. Nuclear run-off assays indicated that ATF effects were due to stimulation of c-fos gene transcription. An increase in c-fos protein levels was correlated with the augmentation of its mRNA in ATF-treated SaOS2 cells. Pretreatment of SaOS2 cells with the protein tyrosine kinase inhibitor herbimycin and recombinant soluble uPA receptor (uPAR) caused a significant reduction in the ability of ATF to induce c-fos expression. These results demonstrate a novel role for uPA in activating early response proto-oncogenes, in particular c-fos, which plays an important role in bone cell growth and differentiation and may be a key factor in the signal transduction pathway of ATF.
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PMID:Induction in human osteoblastic cells (SaOS2) of the early response genes fos, jun, and myc by the amino terminal fragment (ATF) of urokinase. 925 35

Grading of the cribriform pattern of prostate cancer is controversial, and the genetic changes are largely unknown. Furthermore, the pathogenetic relationship between the cribriform pattern of high-grade prostatic intraepithelial neoplasia (PIN) and cribriform carcinoma is poorly understood. We used fluorescence in situ hybridization with centromere-specific probes for chromosomes 7, 8, 10, 12, and Y and a region-specific probe for c-myc to evaluate genetic changes in matched foci of high-grade PIN (48 foci) and prostatic carcinoma (71 foci) in 25 whole-mount radical prostatectomy specimens from patients with metastatic cancer. These cases included 10 foci of cribriform PIN and 10 foci of cribriform cancer. Numeric chromosomal anomalies were found in 67 and 68% of the high-grade PIN and carcinoma foci, respectively. Extra copies of the c-myc gene were identified in 52 and 44% of the high-grade PIN and carcinoma foci, respectively. The cribriform pattern of cancer had a higher percentage of foci with gain of chromosomes 7, 12, and Y, loss of chromosome 8, and extra copies of c-myc gene than other Gleason Primary Patterns 3 and 4; there was no difference, however, for all paired comparisons of genetic changes between the cribriform pattern of cancer and Gleason Primary Pattern 5 cancer. Cribriform PIN and cribriform cancer generally exhibited similar anomalies, although the percentage of foci with gain of chromosomes 10 and 12 was higher in cribriform cancer. Our results indicate that the cribriform pattern of prostate cancer shares genetic changes with Gleason Primary Pattern 5 and that both contain more genetic changes than the cribriform pattern of PIN. These findings suggest that the cribriform pattern of prostate cancer has biologic similarity with Gleason Pattern 5 carcinoma and that the cribriform pattern of PIN is closely associated with the cribriform pattern of prostatic carcinoma.
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PMID:Detection of chromosomal anomalies and c-myc gene amplification in the cribriform pattern of prostatic intraepithelial neoplasia and carcinoma by fluorescence in situ hybridization. 938 62


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