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)

Shessel et al. (Invest. Urol., 17: 529-533, 1980) have reported previously that the serially transplantable Dunning R-3327-G rat prostatic, adenocarcinoma grows faster in intact versus castrated male rats. The present study has demonstrated that this is because the G tumor is composed of androgen-independent but -sensitive prostatic cancer cells. The inclusion that G tumor cells are androgen independent is based upon the observations that these cells are capable of growing following inoculation into castrated male rats and that castration of intact male rats bearing established G tumors induces neither regression of tumor volume nor cessation of the continuous growth of the tumor. The G tumor cells, while being androgen independent, are, however, highly sensitive to androgen for their maximal rate of tumor growth. This androgen sensitivity is demonstrated by the fact that the G tumor cells can be reversibly shifted to a faster or slower growth rate simply by manipulation of the host androgen status. The androgen sensitivity of G tumor growth rate is unusual in that it is not due to androgenic stimulation of cell division but to androgen-induced inhibition of G tumor cell loss (i.e., the rate of G tumor cell loss is reduced by over 50% when androgen is present). The androgen sensitivity of G tumor cell loss is also unusual in that, due to the low level of 5 alpha-reductase activity of the G tumor, the predominant intracellular androgen responsible for this inhibition in untreated intact hosts appears to be testosterone and not dihydrotestosterone (DHT). In castrated rats, however, exogenous treatment with DHT is equally as effective as exogenous testosterone in inhibiting G tumor cell loss. These results suggest that G tumor cells are sensitive to either testosterone or DHT but that in untreated intact hosts little DHT is formed by the tumor cells.
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PMID:Unusual androgen sensitivity of the androgen-independent Dunning R-3327-G rat prostatic adenocarcinoma: androgen effect on tumor cell loss. 709 58

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.
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PMID:Inverse relationships between cell proliferation and basal or androgen-stimulated apolipoprotein D secretion in LNCaP human prostate cancer cells. 752 88

LNCaP is an androgen-sensitive human prostatic cancer cell line. The effect of androgen on these cells is characterized by a bell-shaped growth response and a dose-dependent induction of prostate-specific antigen (PSA) production. The present study was carried out to gain further insight into the effect of androgen on LNCaP. Cells were cultured in phenol red-free RPMI-1640 supplemented with 10% charcoal-stripped fetal bovine serum, with concentrations of dihydrotestosterone (DHT) ranging from 0-10(-7) M, in a 4-day culture system. A bell-shaped growth response was reproduced with a peak level of cell count at 10(-10) M DHT. PSA secretion from these cells did not increase significantly until the DHT level in the medium reached 10(-9) M. A progressive increase in PSA secretion was observed at higher DHT concentrations accompanied with a progressive decline in cellular proliferation. The results of immunocytochemical analysis of PSA localization indicated that the proportion of cells with positive staining for PSA also increased with increasing concentrations of DHT. Analysis of androgen receptors, as determined by both immunocytochemistry and Western blot analysis, showed a decline in nuclear androgen receptor at low concentrations of DHT and an increase in the amount of receptor protein at high concentrations. These results indicated that the androgen-induced bell-shaped growth response in LNCaP cells represented the manifestation of two different cellular events in dose-related manner: cellular proliferation at low DHT concentrations and increased production of PSA at high DHT concentrations.
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PMID:Regulation of proliferation and production of prostate-specific antigen in androgen-sensitive prostatic cancer cells, LNCaP, by dihydrotestosterone. 753 Jun 53

The mechanism of antiandrogenic activity of vinclozolin (3-(3,5-dichlorophenyl)-5-methyl-5-vinyloxazolidine-2,4-dione), a dicarboximide fungicide under investigation for its potential adverse effects on human male reproduction, was investigated using recombinant human androgen receptor (AR). The two primary metabolites of vinclozolin in plants and mammals are M1 (2-[[3,5-dichlorophenyl)-carbamoyl]oxy]-2-methyl-3-butenoic acid) and M2 (3',5'-dichloro-2-hydroxy-2-methylbut-3-enanilide). Both metabolites, in a dose-dependent manner, target AR to the nucleus and inhibit androgen-induced transactivation mediated by the mouse mammary tumor virus promoter. M2 is a 50-fold more potent inhibitor than M1 and only 2-fold less than hydroxyflutamide. In the presence of dihydrotestosterone (50 nM), M2 (0.2-10 microM) inhibits androgen-induced AR binding to androgen response element DNA. In the absence of dihydrotestosterone, concentrations of 10 microM M2 or hydroxyflutamide promote AR binding to androgen response element DNA and activation of transcription. Agonist activities of M2 and hydroxyflutamide occur at 10-fold lower concentrations with the mutant AR (Thr877 to Ala) endogenous to LNCaP human prostate cancer cells. The results indicate that androgen antagonists can act as agonists, depending on ligand binding affinity, concentration, and the presence of competing natural ligands.
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PMID:Androgen receptor antagonist versus agonist activities of the fungicide vinclozolin relative to hydroxyflutamide. 765 17

Both androgen and antiandrogen treatments enhance the proliferation rate of the hormone-dependent prostate cancer cell line LNCaP, expressing a mutated androgen receptor (AR). We studied the modification of the expression of epidermal growth factor (EGF), of its receptor (EGF-R), and of androgen receptor (AR) in the LNCaP cell line, under basal conditions and during androgen (R1881) and antiandrogen hydroxy-flutamide (OH-FLU) treatment. After prolonged R1881 administration, a marked increase of EGF release was observed, completely blocked by the addition of OH-FLU. The Scatchard plot analysis of EGF-R binding revealed two classes of binding sites with high and low affinity. The administration of OH-FLU alone or combined with R1881 did not modify the affinity constants, while the low-affinity component disappeared after androgen administration. Both androgen and antiandrogen administration led to a significant increase of the EGF-R high-affinity component. AR mRNA and protein levels were downregulated by R1881 treatment. Following OH-FLU administration, AR mRNA was slightly downregulated, and there was not a strict parallelism between AR mRNA levels and AR binding capacity. When combined with R1881, OH-FLU partially counteracted the androgen-induced AR downregulation. Our data show that EGF-R binding capacity is the only parameter constantly raised in cell proliferation with respect to quiescent cells, and highlights the nonunivocal action of OH-FLU on androgen-induced effects.
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PMID:Androgenic and antiandrogenic control on epidermal growth factor, epidermal growth factor receptor, and androgen receptor expression in human prostate cancer cell line LNCaP. 778 69

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

Human androgen receptor (hAR) is a ligand-dependent transcription factor that mediates androgen-induced actions on target tissues. Transfection studies in the human prostate cancer cell line LNCaP examine the ability of dihydrotestosterone (DHT), hydroxyflutamide (HO-FLU), cyproterone acetate (Cypro.A), and RU 23908-10 to stimulate or to inhibit the transcription activation of mouse mammary tumor virus-bacterial chloramphenicol acetyltransferase (MMTV-CAT). DHT stimulated transcription activation of MMTV-CAT gene in LNCaP cells in a dose-dependent manner. HO-FLU, Cypro.A, and RU 23908-10, though only partially, also stimulated the transcription activation of MMTV-CAT. Despite this, 100- to 1,000-fold molar excess of all antiandrogens inhibited the agonistic activity of 10 nM DHT in this system. Receptor binding assays confirmed that HO-FLU, Cypro.A, and RU 23908-10 competed with DHT for AR binding in LNCaP cells. Western blot analysis using AR antipeptide antibodies raised in rabbits revealed the presence of two AR protein bands in LNCaP cells, following treatment with antiandrogens. Increasing doses of HO-FLU stimulated the expression of the 114-kDa AR by 2.5-fold, but did not affect the 108-kDa AR. Increasing doses of Cypro.A and RU 23908-10 decreased the levels of both the 114-kDa and the 108-kDa AR. Although the exact nature of 108-kDa and 114-kDa AR in LNCaP cells is still unknown, these data suggest that the regulatory actions of each individual antiandrogen on AR expression in LNCaP cells may be different.
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PMID:Antiandrogens inhibit human androgen receptor-dependent gene transcription activation in the human prostate cancer cells LNCaP. 814 66

A full length human androgen receptor complementary DNA was introduced into androgen receptor-negative PC-3 cells to determine if androgen sensitivity could be established in this cell line and to assess what influence, if any, androgen exposure would have on the growth of these cells. The androgen receptor complementary DNA was inserted into pSG5 in the region controlled by the SV40 promoter. This construct was cotransfected with pSR1neo into PC-3 cells and stably transfected cells were selected and screened for the expression of the androgen receptor. Active expression of the receptor was demonstrated by Western blotting using a rabbit anti-androgen receptor antiserum and by [3H]methyltrienolone binding to cytosol extracts. Saturation ligand-binding analysis revealed the presence of a single class, high affinity (Kd = 0.122 nM) androgen-binding site in cytosol extracts of transfected cells but not in extracts from mock-transfected cells. In cells expressing the transfected androgen receptor, androgen decreased the proliferation rate and cloning efficiency and induced a more differentiated phenotype. These results demonstrate that PC-3 cells have retained the mechanisms required to respond to the activated androgen receptor and that the loss of androgen sensitivity in these cells is due to the lack of functional androgen receptor. This also provides a technique for determining whether androgen-resistant tumor cells contain functional androgen receptors or whether androgen sensitivity is due to abnormalities in downstream signaling pathways. The apparent androgen-induced decreased malignant state of these transfected cells suggests new directions for the treatment of prostate cancer.
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PMID:Androgen-induced inhibition of cell proliferation in an androgen-insensitive prostate cancer cell line (PC-3) transfected with a human androgen receptor complementary DNA. 844 9

There is increasing evidence that growth and differentiation of prostatic carcinoma cells may be modulated not only by androgens and growth factors but also by vitamin D, retinoids, and phenylacetate (PA). The latter agonists may have a role in the prevention and therapy of prostate cancer but their exact therapeutic potential remains unclear. Since both retinoids and vitamin D act via nuclear receptors, the same way androgens do, we studied the interactions of these compounds with androgen-induced proliferation and differentiation using LNCaP cells as a model of androgen-responsive tumor cells. PA was included because of its suspected different mode of action [H3]-thymidine incorporation was used as a measure of proliferative activity, secretion of prostate-specific antigen (PSA) as a measure of differentiated function. The present data show that 1alpha,25-dihydroxycholecalciferol (VD3), all-trans retinoic acid (atRA), 9-cis retinoic acid (9cRA), and PA stimulated LNCaP cell-differentiated function in the presence or absence of androgens. The effects on cell growth were more complicated. In the absence of androgens growth stimulatory effects were observed for the retinoids and under some conditions for VD3. These effects were limited, however, and tended to be more pronounced at low cell densities. In the presence of androgens nearly exclusively growth inhibitory effects were observed. On a molar basis VD3 was the most effective antiproliferative agonist (ED50 = 10(-9) M). It completely neutralized the stimulatory effects of androgens. Growth inhibition was not due to a decrease in the concentration of androgen receptor: whereas atRA, 9cRA, and PA did not alter androgen receptor levels, VD3 provoked a twofold increase. Neither in the presence nor in the absence of androgens did we observe any cooperativity in the growth stimulatory or inhibitory effects of VD3, atRA, or 9cRA. To test whether treatment with any of the studied agonists resulted in a phenotypic reversion and sustained growth arrest, LNCaP cells were pretreated with VD3, atRA, 9cRA, or PA for 6-12 days and reseeded at equal densities as untreated cells. In all cases tested [3H]-thymidine incorporation was restored within 6 days suggesting that none of these compounds caused irreversible growth inhibition.
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PMID:Control of LNCaP proliferation and differentiation: actions and interactions of androgens, 1alpha,25-dihydroxycholecalciferol, all-trans retinoic acid, 9-cis retinoic acid, and phenylacetate. 862 21

Transglutaminases (TGases) are calcium-dependent enzymes catalysing the post-translational cross-linking of proteins. In the prostate at least two TGases are present, the ubiquitously expressed tissue-type TGase (TGC), and a prostate-restricted TGase (TGP). This paper deals with the molecular cloning and characterization of the cDNA encoding the human prostate TGase (hTGP). For this purpose we have screened a human prostate cDNA library with a probe from the active-site region of TGC. The largest isolated cDNA contained an open reading frame encoding a protein of 684 amino acids with a predicted molecular mass of 77 kDa as confirmed by in vitro transcription-translation and subsequent SDS/PAGE. The hTGP gene was tissue-specifically expressed in the prostate, yielding an mRNA of approx. 3.5 kb. Furthermore, a 3-fold androgen-induced upregulation of hTGP mRNA expression has been demonstrated in the recently developed human prostate cancer cell line, PC346C. Other well established human prostate cancer cell lines, LNCaP and PC-3, showed no detectable hTGP mRNA expression on a Northern bolt. The gene coding for prostate TGase was assigned to chromosome 3.
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PMID:Tissue specific and androgen-regulated expression of human prostate-specific transglutaminase. 864 75


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