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)

Highly potent LH-releasing hormone (LHRH) agonists have been recently introduced in therapy for the treatment of the carcinoma of the prostate, an androgen-dependent pathology. These peptides are believed to act mainly by inhibiting the pituitary-testicular axis and, consequently, by reducing testosterone levels. The recent observation that binding sites for LHRH analogs are present on prostatic tumor tissue suggests that these drugs could also act directly on the tumor. To verify this hypothesis, the effects of two potent LHRH agonists [Zoladex (Z) and Buserelin (B)] have been studied on the proliferation of the human prostatic cancer cell line LNCaP (lymph node carcinoma of the prostate). LNCaP cells were treated for 9 days with different doses of either Z or B (concentrations from 10(-12)-10(-6) M). Both analogs significantly inhibited cell proliferation at doses between 10(-9)-10(-6) M. The antiproliferative action of the two LHRH agonists was shown to be dose dependent, with IC50 values of 0.82 and 1.79 nM for Z and B, respectively. A similar treatment with B was without any significant effect on the proliferation of a mouse embryo fibroblast cell line (Swiss 3T3), which was used as a nontumoral control. The inhibitory action of both LHRH agonists (10(-8) M) on LNCaP cell proliferation was completely antagonized by the simultaneous treatment of the cells with a potent LHRH antagonist (Nal-Arg-LHRH; 10(-8) M); when given alone at the dose selected, the antagonist did not affect cell growth. These results clearly suggest that the antiproliferative effect of LHRH agonists on LNCaP cells may be mediated by specific receptors. The presence of binding sites for [125I]B was consequently demonstrated on the membranes of LNCaP cells cultured in a medium containing charcoal-stripped fetal calf serum, i.e. in the absence of steroids. The affinity of these binding sites for the ligand was lower than that observed for the same receptors on rat pituitary membranes. To clarify the mechanism of the antiproliferative action of the LHRH agonists, the effects of both Z and B on the incorporation of [3H]thymidine and [14C]methionine into LNCaP cells were investigated. During a short incubation period (3 h), the two LHRH agonists rapidly inhibited [3H]thymidine incorporation into the cells. The same treatment did not affect the incorporation of [14C]methionine into proteins.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Antiproliferative effects of luteinizing hormone-releasing hormone agonists on the human prostatic cancer cell line LNCaP. 132 49

We screened human prostate cancer tissues for the presence of somatic mutations in the hormone binding domain of the androgen receptor (AR) gene. Exons E-H were amplified from genomic DNA using the polymerase chain reaction and analyzed by denaturing gradient gel electrophoresis (DGGE), which separates DNA fragments that differ by only a single base. We detected a mutation in exon E of the hormone binding domain in 1 of 26 specimens of untreated organ-confined stage B prostate cancer. The mutation was not detectable in peripheral blood lymphocyte DNA. Lymphocyte DNA (wild-type AR) migrated in DGGE as a single band. The tumor DNA migrated in DGGE as four bands, consistent with the presence of cells with mutant AR plus cells with wild-type AR and indicating that the tumor contained a somatic mutation. To our knowledge, a somatic AR gene mutation has not been reported previously. Sequencing revealed a G----A substitution in codon 730, changing valine to methionine. Codon 730 is in a region highly conserved among all steroid receptors. The abundance of the mutated fragment (about 50% of the DNA in the specimen) indicates its presence in cells with a growth advantage. A somatic mutation could be detected by DGGE if it represented at least 10% of the sample. Failure to detect mutations in other specimens analyzed may be due to this limit of sensitivity, the presence of mutations in other parts of the AR, or a low frequency of mutations in early stage disease.
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PMID:Androgen receptor gene mutations in human prostate cancer. 163 Nov 25

Androgens mediate their effects through an intracellular receptor that is a member of the steroid/thyroid hormone family of receptors. The expression of this protein is tightly regulated in different tissues and among cell types within a single tissue. To define the mechanisms controlling the expression of the androgen receptor, we have isolated and characterized the promoter of the androgen receptor gene in the human prostate cell line LNCaP. The major site of transcription initiation is approximately 1.1 kilobases upstream of the initiator methionine of the androgen receptor protein. The promoter region lacks typical "TATA" and "CAAT" sequence motifs but lies in a GC-rich region and contains a putative Sp1 binding site characteristic of a "housekeeping" promoter and a 44-base segment composed of alternating adenosine and guanosine residues. S1 nuclease protection analyses indicate that the same promoter is employed both in human tissues (prostate, testes), in genital skin fibroblasts, in T47D and MCF-7 breast cancer cells, and in LNCaP prostate cancer cells.
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PMID:Expression of the human androgen receptor gene utilizes a common promoter in diverse human tissues and cell lines. 238 Jan 87

To evaluate the role of small amounts of DHT in prostate tissue as a stimulus to epithelial cell growth (protein synthesis) we studied tissue from patients given various androgen-blocking drugs prior to transurethral resection of the prostate (TURP) and measured epithelial protein synthesis and DHT in the tissue specimens. We also studied the effects on stromal cell protein synthesis of an antiestrogen, tamoxifen. Test drugs prior to TURP included Megace 160 mg per day, Megace 160 mg per day plus Tamoxifen 40 mg per day, Megace 160 mg a day plus ketoconazole 1200 mg per day and tamoxifen 40 mg/day. The tissue was processed immediately and epithelial and stromal cells separated by digestion of tissue with 0.5% collagenase. After separation, epithelial cells were labeled with either [3H]leucine or L-[35S]methionine. Stromal cells were labelled with [3H]proline. DHT was measured in whole prostate tissue. Megace alone and Megace plus tamoxifen significantly decreased both [3H]leucine incorporation into protein and tissue concentration of DHT; Megace plus ketoconazole significantly decreased L-[35S]methionine incorporation into protein and DHT. Tamoxifen significantly decreased stromal protein synthesis. When the data correlating DHT with epithelial protein synthesis using both labeling techniques were combined, the curves were parallel and a strong correlation was noted between DHT and protein synthesis over a wide range of values (P less than 0.001). These results suggest that in hormone-dependent prostate cancer even small amounts of prostate DHT such as may occur from adrenal androgens following castration may significantly stimulate growth of the tumor epithelial cells. Since tamoxifen decreased stromal protein synthesis, estrogen is likely a significant growth stimulus to the increased stromal mass characteristic of benign prostatic hypertrophy.
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PMID:Effect of antiandrogen and/or antiestrogen blockade on human prostate epithelial and stromal cell protein synthesis. 243 6

To evaluate the role of small amounts of prostatic tissue dihydrotestosterone (DHT) as a stimulus to epithelial cell protein synthesis, we studied tissue from 27 patients given various androgen-blocking drugs for 1 week before transurethral resection of the prostate (TURP) and measured epithelial protein synthesis and DHT levels in the tissue specimens. Test drugs before TURP included megestrol acetate 160 mg per day, with and without Tamoxifen 40 mg per day, or ketoconazole 1200 mg per day. The tissue was processed immediately and epithelial cells separated by digestion of tissue with 0.5% collagenase. After separation, epithelial cells were labelled with either 3H-leucine or L-35S-methionine. The DHT level was measured in whole prostatic tissue. Megestrol acetate alone and with tamoxifen significantly decreased both the incorporation of 3H-leucine into protein and the tissue concentration of DHT; megestrol acetate plus ketoconazole significantly decreased L-35S-methionine incorporation into protein and the DHT level. When the data correlating DHT with protein synthesis using both labelling techniques were combined, the curves were parallel and a strong correlation was noted between DHT and protein synthesis over a wide range of values (P less than 0.001). These results suggest that in hormone-dependent prostatic cancer even small amounts of prostatic DHT such as may occur from adrenal androgens following castration may significantly stimulate protein synthesis of the tumour epithelial cells.
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PMID:Relationship between human prostatic epithelial cell protein synthesis and tissue dihydrotestosterone level. 366 14

The effects of somatostatin-14 (S) on the proliferation of the human prostatic cancer cell line (LNCaP, lymph node carcinoma of the prostate) and on the amount of proteins secreted by these cells have been studied. LNCaP cells were treated for 3 days with different doses of S. The hormone significantly inhibits cell proliferation at doses comprised between 0.4 and 2 nmol, as indicated by a significant decrease in the incorporation of 3H-thymidine as well as in the uptake of [alpha-32P]dATP. The direct antiproliferative effect of S is reversible, since cell proliferation returns to normal 4 days after withdrawal of the hormone from the medium. This action of S is not due to cytotoxic side-effects, since no changes in the incorporation of 35S-methionine are observed. Total RNA and protein synthesis do not appear to be modified by the hormone in vitro. The hormone probably exerts its antiproliferative effect on LNCaP cells by stimulating phosphotyrosyl protein phosphatases, since the inhibition of growth induced by S (1 nmol) is reversed by sodium vanadate (2 and 4 mumol), a potent inhibitor of the process of tyrosine dephosphorilation. In addition, S (1 nmol/L) induces a significant decrease in the amounts of proteins secreted by LNCaP cells. Also the antisecretory action of S seems to be mediated by the activation of phosphotyrosyl protein phosphatases, since sodium vanadate is able to reverse the action of S on this parameter. In conclusion, the present data suggest for the first time that S exerts a direct inhibitory effect on LNCaP cell proliferation and protein secretion, two effects probably mediated by the activation of phosphotyrosyl protein phosphatases.
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PMID:Direct inhibitory effect of somatostatin on the growth of the human prostatic cancer cell line LNCaP: possible mechanism of action. 769 Mar 58

We are investigating the role of the early response transcription factor, nerve growth factor inducible A gene (NGFI-A), as a modulator of retinoblastoma (RB) gene transcription in prostate cells. Examination of the RB promoter reveals a novel element GCGGGGGAG located at nucleotides 152-144 upstream of the methionine initiation codon. This sequence shares strong homology with the consensus NGFI-A binding element GCGGGGGCG varying by a single nucleotide. In DNA binding assays, an NGFI-A fusion protein and the native protein product of the NGFI-A gene purified from prostate cancer cells bound specifically to an oligonucleotide containing the RB promoter element. Gene expression studies in rat ventral prostate demonstrated a 1.9-fold increase in RB mRNA following castration that parallels a 2.7-fold induction of NGFI-A mRNA. In summary, the in vitro DNA binding data and the transient coregulation of rat NGFI-A and RB following castration suggests that the RB gene may be transcriptionally regulated by NGFI-A in prostate cells.
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PMID:Prostatic nerve growth factor inducible A gene binds a novel element in the retinoblastoma gene promoter. 824 9

Prostate cancer frequently metastasizes to bone, and we propose that this process may be facilitated by the adhesion of metastatic cells to bone-derived type I collagen. We examined collagen receptor function and regulation in osteotropic PC-3 human prostatic carcinoma cells. PC-3 cell adhesion to immobilized human type I collagen was promoted by Mn2+ and Mg2+ ions and was RGD-independent. Antibodies directed against beta1 or alpha2 integrin subunits inhibited adhesion to collagen by 90% and 53%, respectively, suggesting involvement of the alpha2 beta1 receptor. Anti-alpha1 or anti-alpha3 antibodies had no effect on adhesion. Flow cytometry and immunoprecipitation of [35S]methionine-labeled cells demonstrated that alpha2 beta1 was the major collagen receptor expressed by PC-3 cells. The pretreatment of PC-3 cells with transforming growth factor-beta1 (TGF-beta1), a major bone-derived growth factor, caused a rapid (2 h) 2-fold increase in the de novo synthesis of alpha2 and beta1 integrin subunits, and also increased by 2- to 3-fold the adhesion and spreading of PC-3 cells on collagen. We conclude that alpha2 beta1 is the major collagen receptor employed by PC-3 cells, and that alpha2 beta1 upregulation by TGF-beta is associated with an increased adhesion and spreading on collagen. The data suggest that exposure of metastatic PC-3 cells to the high levels of TGF-beta in bone may promote their ability to adhere to bone-derived collagen, which may thereby facilitate the localization of metastatic cells in the skeleton.
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PMID:Transforming growth factor beta upregulates the integrin-mediated adhesion of human prostatic carcinoma cells to type I collagen. 900 5

Methionine (MET) is required for cell metabolism. MET endogenously synthesized from homocysteine (HCY) supports the proliferation of normal cells, but not that of numerous malignant cells, as shown previously. MET starvation should have an anti-tumour effect, and its deleterious effects on the hosts might be prevented by HCY. Anti-tumour effects of MET starvation must be reinforced by ethionine (ETH), a MET analogue. MET dependency of PC-3, a human prostate cancer cell line, was studied in vitro. Proliferation of PC-3 cells, cultivated in MET-free medium, was 29% compared with growth in MET+HCY- medium. Addition of HCY to MET-free medium increased the proliferation rate to 56%. The concentration of ETH required to decrease the PC-3 cell proliferation rate to 50% (IC50) was 0.5 mg ml(-1) in MET-HCY- medium. ETH-induced inhibition was abolished by MET addition and was reinforced by HCY. PC-3 cell cycle was blocked in the S-G2-phase after 30 h culture in the absence of MET; this blockage was not reversed by addition of HCY. ETH at the IC50 in MET-HCY+ medium blocked DNA replication. Apoptotic cells appeared after 30 h incubation in MET-HCY+ medium only when ETH was added. ATP pools were decreased after 15 h of culture in MET-free medium. In vivo, MET starvation was obtained by feeding tumour-bearing mice a diet containing a synthetic amino acid mixture as the protein supply, in which HCY replaced MET. Given to nude mice bearing xenografted PC-3, from day 1 after grafting and for 3 weeks, this diet inhibited tumour growth (34% on day 20, P < 0.007); this effect was potentiated by ETH (200 mg kg(-1) day(-1) i.p.) (56% on day 20, P < 5 x 10(-5)). The differences between the effects of these two treatments were significant (P < 0.017) and optimal on day 20. These data showed that combination of ETH and HCY slowed the proliferation of prostate cancer cells in vitro and in vivo, decreased ATP synthesis and caused cell cycle arrest and apoptosis. Experimental therapy based on cancer cell MET metabolism deficiency could be efficient for treating advanced prostate cancers refractory to current therapies.
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PMID:Growth of methionine-dependent human prostate cancer (PC-3) is inhibited by ethionine combined with methionine starvation. 918 75

Since loss of heterozygosity on 8p22-p21.3 has been found frequently in prostate cancer, the status of a candidate tumor suppressor gene named PRLTS gene, recently cloned from the same region in some human malignancies, was examined in the present study. DNAs were isolated from 69 Japanese prostate cancer patients (37 localized and 32 cancer-death cases). Loss of heterozygosity at this gene locus was observed in 15 of 36 (42%) localized prostate cancer patients and 22 of 32 (69%) cancer-death patients. One cancer-death patient had a missense mutation, ACG-->ATG (Thr-->Met) at codon 64 in metastatic tumor tissues of pelvic lymph node and liver, and these tissues showed loss of the homologous allele, indicating that "two-hit" mutation of the PRLTS gene had occurred in this case. The others did not show any mutation, regardless of the presence or absence of loss of heterozygosity. Although loss of heterozygosity at the PRLTS gene locus is a relatively common abnormality, mutation of this gene is rare in prostate cancer.
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PMID:PRLTS gene alterations in human prostate cancer. 919 31


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