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Query: UNIPROT:P06889 (Mol)
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Daily subcutaneous administration of 50 micrograms of the luteinizing hormone-releasing hormone (LHRH) agonist [D-Trp6]LHRH ethylamide in adult dogs causes a transient increase in the serum testosterone (T) concentration which reaches a maximum at 200% above control on days 2-4 of treatment and progressively decreases to 7% of the pretreatment value on day 21, the last time interval studied. After a transient increase, the concentration of serum bioactive luteinizing hormone (LH) was progressively decreased on days 11 and 19, thus suggesting that in analogy with human findings, the loss of LH bioactivity is responsible for the inhibition of testicular steroidogenesis induced in the dog by LHRH agonists. Of major significance is the finding that the changes in serum T levels observed during the first 3 weeks of treatment, as well as the complete inhibition of the intratesticular concentration of sex steroids observed at the end of this period of treatment with the LHRH agonist were not affected by simultaneous administration of flutamide (125 mg per os every 8 h). Such findings indicate that at the dose used, the LHRH agonist is in full control of gonadotropin secretion, thus completely overcoming feedback influences. Since the administration of the antiandrogen flutamide does not decrease the efficacy of the LHRH agonist as blocker of testicular androgen biosynthesis, the present data support the use of a pure antiandrogen in order to neutralize the effect of the transient rise in testicular androgen secretion which always accompanies the first days of treatment with LHRH agonists in patients with advanced prostate cancer.
Mol Cell Endocrinol 1988 Mar
PMID:A pure antiandrogen does not interfere with the LHRH agonist-induced blockade of testicular androgen secretion in the dog. 328 22

The role of cytoskeletal structure in the alteration of cell shape, multinucleation, and intracellular transport of human prostatic carcinoma cells DU 145 was investigated by light microscopy, scanning and transmission electron microscopy, and by immunofluorescence microscopy. It was confirmed that alterations in cell shape and surface topography, multinucleation, and intracellular transport of these cultured cells were regulated by a microfilament system composed of actin. The presence of prekeratin confirmed the epithelial nature of these cells. It was noted for the first time that these cells were highly motile and contained fewer microtubules, a moderate amount of intermediate filaments, and a large amount of microfilaments. "Displastic" cells were quite common in long-term culture. DU 145 cells are excellent in vitro models for further research on human prostatic cancer cells.
Exp Mol Pathol 1986 Apr
PMID:Pleomorphism of human prostatic cancer cells (DU 145) in culture--the role of cytoskeleton. 369 42

The androgen receptor (AR) is a ligand-dependent DNA transcription factor that binds androgens which cause masculinisation of the developing male fetus. Classical abnormalities of receptor function result in the syndrome of androgen resistance, with resultant failure of normal male differentiation. In more recent years, however, mutations in the AR gene have been described in a number of diverse clinical conditions, from male infertility to prostate and breast cancer through to a form of motor neurone disease (Kennedy's disease). This review discusses the various AR gene mutations found in androgen insensitivity syndrome (AIS) and the other conditions described above, and relates how different mutations, or disruption of different functional domains, contributes to the various phenotypes. Mutations that cause complete AIS usually disrupt the DNA or steroid binding ability of the receptor. In partial AIS, mutations generally decrease receptor affinity for ligand, affect thermostability of the protein, or affect the ability of the receptor to activate transcription of responsive genes. Isolated mutations occur in the steroid binding domain of the receptor in prostate cancer, and many cancers have an identical mutation. Similarly, in the two cases of male breast cancer in which AR gene mutations have been described, the mutations in the DNA binding domain of the receptor are alike. In Kennedy's disease a trinucleotide repeat expansion occurs in exon A of the AR gene, which appears to affect ability of the receptor to bind ligand and activate transcription, although the mechanism of neuronal degeneration remains unknown.
Mol Cell Endocrinol 1995 Aug 11
PMID:Defects of androgen receptor function: from sex reversal to motor neurone disease. 748 16

Enhanced expression of the epidermal growth factor receptor (EGFR) or its ligands, epidermal growth factor (EGF) and transforming growth factor alpha (TGF-alpha) can increase signalling via receptor-mediated pathways which may lead to excessive proliferation and cellular transformation. Such autocrine regulation of growth has been demonstrated for prostate cancer cell lines in culture but its role in prostate cancer in vivo has not been established. To assess the potential of such a mechanism, we have examined the pathway components in prostate carcinomas (CaP) in comparison with non-malignant benign prostatic hyperplasias (BPH). In the present study, we investigate the dosage, structure and expression of EGF, TGF-alpha and EGFR genes in a series of 34 human prostate samples and 3 prostate cancer cell lines. All of the samples contained transcripts from each of the genes. The expression of pre-pro-TGF-alpha mRNA and pre-pro-EGF mRNA were significantly higher in CaP (n = 13) than BPH (n = 21) specimens (p < 0.05). The androgen-responsive prostatic carcinoma cell line, LNCaP, expressed high levels of EGF mRNA while the androgen-independent DU145 and PC-3 cell lines expressed high levels of TGF-alpha mRNA and EGFR mRNA. In general, overexpression of these mRNAs was not associated with amplification or detectable gene rearrangement; only DU145 cells demonstrated any alteration in these genes, with apparent amplification of the TGF-alpha gene. Relative to BPH, all prostate carcinomas and cell lines studied had elevated levels of mRNA for one or both mRNA coding for the ligands for EGFR.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Cell Biochem 1993 Sep 22
PMID:Expression of mRNA for epidermal growth factor, transforming growth factor-alpha and their receptor in human prostate tissue and cell lines. 750 78

Pathways of testosterone metabolism in tissue slices and cell suspensions of human benign hyperplastic prostate (BPH) tissue and human prostate cancer cell lines (DU145, HPC-36M, PC-3/MA2 and LNCaP) were investigated. Thin layer chromatography analysis was used to identify the following tritiated metabolites: testosterone, 5 alpha-dihydrostestosterone (DHT), 5 alpha-androstane-3 alpha/3 beta-17 beta-diol (androstanediols), 4-androstene-3,17-dione (androstenedione) and 5 alpha-androstanedione. The predominant pathway for testosterone metabolism in BPH was via 5 alpha-reductase producing 5 alpha-dihydrotestosterone (71% and 75% total metabolites in slices and suspensions incubated for 24 h, respectively). The cancer cell lines DU145 and HPC-36M resembled BPH by metabolizing testosterone predominantly to DHT (68% and 82% total metabolites, respectively), although the rate of metabolism was much lower in the cell lines (0.099 and 0.05 pmol testosterone/mg protein/h in DU145 and HPC-36M) compared to the BPH cell suspensions (6.4 pmol testosterone/mg protein/h). In contrast, PC-3/MA2 contained high 17 beta-HSD activity forming large amounts of 4-androstene-3,17-dione (84% total metabolites), converting testosterone at a rate faster (12.8 pmol testosterone/mg protein/h) than the BPH cell suspensions. LNCaP rapidly converted testosterone exclusively to a glucuronide conjugate (7.4 pmol testosterone/mg protein/h), although after incubation with [3H]-4-androstene-3,17-dione, 5 alpha-reductase activity was demonstrated. LNCaP was the only cell line whose growth and colony-forming ability was stimulated by testosterone and DHT. BPH and all the cell lines tested had 5 alpha-reductase activity, but only the prostate tissue and the cell lines DU145 and HPC-36M converted testosterone predominantly to DHT.
J Steroid Biochem Mol Biol 1994 Aug
PMID:Comparison of testosterone metabolism in benign prostatic hyperplasia and human prostate cancer cell lines in vitro. 751 39

We have recently demonstrated that the biphasic action of androgens on LNCaP cell proliferation is opposite to their effect on apolipoprotein D (apo-D) secretion, the stimulation of apo-D secretion being associated with a steroid-induced inhibition of cell proliferation. To further characterize the control of apo-D expression in LNCaP cells, we studied basal as well as androgen-induced apo-D secretion in slowly proliferating, low-passage (LP; 20-29th) and rapidly proliferating high-passage (HP; 111-117th) cell cultures. For comparison, the androgen-induced stimulation of prostate specific antigen secretion was also investigated in LP and HP cell cultures. In the absence of androgens, basal cell proliferation of HP cells was significantly higher than that of LP cells, whereas apo-D secretion was higher in LP cells than in HP cells. Furthermore, the biphasic action of dihydrotestosterone and of the synthetic androgenic compound R1881 on apo-D release and cell proliferation was observed in both LP and HP cells. The stimulation of apo-D secretion was inversely related to that of cell proliferation and influenced by cell density. The inhibition of basal and androgen-induced cell proliferation by the calcium channel blocker nifedipine was also associated with an increase in apo-D secretion. The amount of PSA released and the sensitivity of its response to R1881 were increased in LP cells compared with HP cells. The present study thus demonstrates, for the first time, that apo-D secretion is inversely correlated to cell proliferation and cell density in the absence as well as in the presence of androgens in both LP and HP LNCaP human prostate cancer cells. This finding suggests that apo-D expression can be modulated not only by steroid hormones, but also by other factors involved in the control of cell proliferation.
J Steroid Biochem Mol Biol 1994 Nov
PMID:Inverse relationships between cell proliferation and basal or androgen-stimulated apolipoprotein D secretion in LNCaP human prostate cancer cells. 752 88

Paclitaxel was examined for its effects on cell survival, internucleosomal DNA fragmentation, and protein isoprenylation in the human prostate cancer cell line PC-3. Treatment of cells with paclitaxel at 5-60 nM for 24 hr resulted in a dose-dependent inhibition of cell viability (IC50, 31.2 nM), which was partially prevented by supplementing the cell culture medium with two nonsterol polyisoprenyl compounds, farnesyl-pyrophosphate (-PP) and geranylgeranyl-PP (3 microM each). Furthermore, agarose gel electrophoresis of DNA extracted from cells treated with paclitaxel (15-60 nM) for 24 hr showed DNA laddering with production of fragments of 180-base pair multiples, indicating the occurrence of apoptotic cell death. Internucleosomal DNA fragmentation by paclitaxel was also detected by a photometric enzyme immunoassay using antihistone antibodies; if culture medium was supplemented with farnesyl-PP and geranylgeranyl-PP (3 microM each), a reduction in mono- and oligonucleosome production was observed. The post-translational incorporation of metabolites of (RS)-[5-3H]mevalonolactone (100 microCi/ml) into prenylated proteins of PC-3 cells was inhibited by paclitaxel at 30 and 60 nM. In addition, the immunoprecipitation of p21ras and p21rap-1 proteins from PC-3 cells exposed to paclitaxel (30 and 60 nM) and labeled with (RS)-[5-3H]mevalonolactone showed a substantial inhibition of the incorporation of farnesyl and geranylgeranyl prenoid groups, respectively, into the aforementioned proteins. These results indicate that the inhibition of protein isoprenylation is a novel component of the complex biochemical effects of the drug and plays an important role in the mechanism of paclitaxel cytotoxicity in PC-3 cells.
Mol Pharmacol 1995 Jun
PMID:Paclitaxel (taxol) inhibits protein isoprenylation and induces apoptosis in PC-3 human prostate cancer cells. 760 48

The crucial role played by androgens in the growth of prostatic carcinoma is now well established. However, the mechanisms of this proliferative action are still poorly understood. Experiments have been performed to clarify: (1) the metabolism of androgens in prostatic tumor cells; and (2) the role played by locally produced growth factors in the autocrine regulation of prostatic tumor cell proliferation and the possible regulation exerted by testosterone (T) on the activity of these factors. These studies have been performed by utilizing the human androgen-responsive prostatic cancer LNCaP cell line. (1) By incubating LNCaP cells with different 14C-labeled androgenic precursors, it has been shown that all the major key enzymes involved in the metabolism of androgens (5 alpha-reductase, 17 beta-hydroxysteroid-oxidoreductase, 3 alpha- and 3 beta-hydroxysteroid-oxidoreductases) are present and active in these cells. In particular, the 5 alpha-reductase, which converts T and delta 4 to DHT and 5 alpha-A respectively, seems to be more active when delta 4 is the substrate, suggesting a preference for this precursor. (2) The hypothesis that LNCaP cells might produce LHRH (or a LHRH-like peptide) has been verified by RT-PCR, performed in the presence of a pair of specific oligonucleotide primers. A cDNA band of the expected size (228 bp), which specifically hybridized with a 32P-labeled LHRH oligonucleotide probe, has been obtained in LNCaP cells. To clarify the possible role played by this factor in the regulation of tumor growth, LNCaP cells, cultured in steroid-free conditions, have been treated with a LHRH antagonist; the treatment resulted in a significant increase of cell proliferation. Taken together, these data indicate that a LHRH (or LHRH-like) growth modulatory system is expressed in LNCaP cells and plays an inhibitory role in the regulation of tumor cell proliferation. This system seems to be regulated in a negative way by steroids. Growth factors endowed with stimulatory activity, such as EGF and TGF alpha, have also been shown to be produced by LNCaP cells. The present studies show that the immunoprecipitation of the EGF receptor with a specific monoclonal antibody (Ab225) reveals a protein band of the expected size (170 kDa) which is phosphorylated even in basal conditions. Moreover, the treatment of LNCaP cells, cultured in serum-free conditions, either with a monoclonal antibody against the EGF receptor, or with immunoneutralizing antibodies against EGF and TGF alpha, results in a significant decrease of cell proliferation.(ABSTRACT TRUNCATED AT 400 WORDS)
J Steroid Biochem Mol Biol 1995 Jun
PMID:Growth of the androgen-dependent tumor of the prostate: role of androgens and of locally expressed growth modulatory factors. 762 87

Male sexual differentiation and development proceed under direct control of androgens. Androgen action is mediated by the intracellular androgen receptor, which belongs to the superfamily of ligand-dependent transcription factors. At least three pathological situations are associated with abnormal androgen receptor structure and function: androgen insensitivity syndrome (AIS), spinal and bulbar muscular atrophy (SBMA) and prostate cancer. In the X-linked androgen insensitivity syndrome, defects in the androgen receptor gene have prevented the normal development of both internal and external male structures in 46,XY individuals. Complete or gross deletions of the androgen receptor gene have not been found frequently in persons with complete androgen insensitivity syndrome. Point mutations at several different sites in exons 2-8 encoding the DNA- and androgen-binding domain, have been reported for partial and complete forms of androgen insensitivity. A relatively high number of mutations were reported in two different clusters in exon 5 and in exon 7. The number of mutations in exon 1 is extremely low and no mutations have been reported in the hinge region, located between the DNA-binding domain and the ligand-binding domain and which is encoded by the first half of exon 4. Androgen receptor gene mutations in prostate cancer are very rare and are reported only in exons 4-8. The X-linked spinal and bulbar muscle atrophy (SBMA; Kennedy's disease) is associated with an expanded length (> 40 residues) of one of the polyglutamine stretches in the N-terminal domain of the androgen receptor.
J Steroid Biochem Mol Biol 1995 Jun
PMID:Androgen receptor mutations. 762 93

The expression of prostatic acid phosphatase (PAcP) in three human prostate carcinoma cell lines including LNCaP, DU 145 and PC-3, was studied to explore its potential role as a marker in the progression of prostate cancer. Although Southern blot analysis suggested the presence of PAcP gene in all three prostate carcinoma cell lines, the Northern blot analysis and the reverse transcriptase-polymerase chain reaction (RT-PCR) assay showed that PAcP mRNA can be detected only in LNCaP cells. As one of the major differences between LNCaP cells and PC-3 as well as DU 145 cells is the androgen-sensitivity of LNCaP cells, we then focused on the influence of PAcP expression by the presence of androgen receptor (AR) in human AR cDNA-transfected PC-3 cells and high passages of LNCaP cells. The results demonstrated that the transfection of human AR cDNA into PC-3 cells did not have any detectable effect on the expression of PAcP. Further, in LNCaP cells, while the level of PAcP mRNA diminished upon passage, the AR mRNA level remained approximately the same. Together, these data suggested that the differential expression of PAcP in different prostate carcinoma cells including high passages of LNCaP cells may occur at the transcriptional level and may have little linkage to the expression of AR.
Mol Cell Endocrinol 1995 Apr 28
PMID:The expression of prostatic acid phosphatase is transcriptionally regulated in human prostate carcinoma cells. 764 50


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