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Androgen

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Guido Verhoeven – 1st expert on this subject based on the ideXlab platform

  • Androgens stimulate fatty acid synthase in the human prostate cancer cell line LNCaP
    Cancer Research, 1997
    Co-Authors: Johannes V. Swinnen, Murielle Esquenet, Karine Goossens, Walter Heyns, Guido Verhoeven

    Abstract:

    In addition to modulation of cell proliferation and stimulation of prostate-specific antigen secretion, one of the most striking effects of Androgens on the human prostate cancer cell line LNCaP is the accumulation of neutral lipids. These lipids are synthesized de novo, suggesting that LNCaP cells express all enzymes required for endogenous lipogenesis and that the expression and/or activity of some of these enzymes is affected by Androgens. One of the key enzymes involved in lipogenesis is fatty acid synthase (FAS), a potential prognostic enzyme and therapeutic target that is found to be frequently overexpressed in a variety of cancers including prostate cancer. Here, using Northern blot analysis, the gene encoding FAS is shown to be abundantly expressed in LNCaP cells and in two other prostate cancer cell lines tested (PC-3 and DU-145). In LNCaP cells, Androgen treatment (10(-8) M R1881) causes a 3-4-fold increase in FAS mRNA levels. Concomitantly with the increase in FAS gene expression, Androgens induce a 10-12-fold stimulation of FAS activity. Effects are dose- and time-dependent and follow courses similar to those of the Androgen induction of lipid accumulation. In support of the involvement of the Androgen receptor, steroid specificity of regulation of FAS activity is in agreement with the aberrant ligand specificity of the mutated Androgen receptor in LNCaP cells. Stimulation of FAS activity is inhibited by the antiAndrogen Casodex (bicalutamide) and is absent in the Androgen receptor-negative cell lines PC-3 and DU-145. Taken together, these data demonstrate that Androgens, mediated by the Androgen receptor, stimulate the expression and activity of FAS and suggest that stimulation of FAS activity represents at least part of the mechanism by which Androgens induce the accumulation of neutral lipids in LNCaP cells.

  • Androgens markedly stimulate the accumulation of neutral lipids in the human prostatic adenocarcinoma cell line lncap
    Endocrinology, 1996
    Co-Authors: Johannes V. Swinnen, Murielle Esquenet, Walter Heyns, P P Van Veldhoven, Guido Verhoeven

    Abstract:

    Microscopic evaluation of LNCaP cells stained with the lipophilic dye Oil red O revealed that Androgens induce a marked stimulation of lipid droplet accumulation. As determined by quantitative analysis of the Oil red O extracted from the stained cells, stimulatory effects of the synthetic Androgen R1881 became apparent at concentrations as low as 10(-11) M. Maximal induction (15-fold) was reached at 10(-8) M. Increases were observed 2 days after hormone addition and were maximal 1 day later. Accumulation of lipid droplets was also induced by mibolerone (another synthetic Androgen) and by the natural Androgens testosterone and dihydrotestosterone. In agreement with the aberrant ligand specificity of the mutated Androgen receptor in LNCaP cells, stimulation of lipid accumulation was also apparent after treatment with progesterone and estradiol. Cortisol and the synthetic glucocorticoid dexamethasone were ineffective. The Androgen antagonist Casodex (bicalutamide) abolished the stimulatory effect of R1881, f…

  • Androgen regulation of the messenger rna encoding diazepam binding inhibitor acyl coa binding protein in the human prostatic adenocarcinoma cell line lncap
    Molecular and Cellular Endocrinology, 1994
    Co-Authors: Johannes V. Swinnen, Murielle Esquenet, Walter Heyns, Wilfried Rombauts, Guido Verhoeven

    Abstract:

    Abstract To study the mechanisms by which Androgens intervene in the regulation of growth and differentiation of human prostatic epithelial cells, cDNA clones encoding putative prostate-secreted proteins were characterized and tested as potential markers for Androgen action. One of the isolated cDNAs expressed diazepam-binding inhibitor/acyl-CoA-binding protein (DBI/ACBP), suggesting that this polypeptide, that has been implicated in a large number of biochemical processes, is expressed and secreted by prostate cells. As demonstrated by Northern blot analysis, the mRNA encoding DBI/ACBP was expressed in prostate tissue and in the three human prostatic adenocarcinoma cell lines tested: LNCaP, PC-3 and DU-145. In Androgen-sensitive LNCaP cells, the synthetic Androgen R1881 stimulated the DBI/ACBP steady state mRNA levels with half maximal effects at a concentration of 0.2 nM. Increases were a maximal 12 h after addition of the synthetic hormone. DBI/ACBP mRNA levels could also be stimulated by the synthetic Androgen mibolerone and by the natural Androgens testosterone and dihydrotestosterone. In agreement with the altered steroid specificity of the Androgen receptor in LNCaP cells, estradiol and progesterone also exerted a stimulatory effect. Cortisol and the synthetic glucocorticoid dexamethasone were without effect. Androgen stimulation of DBI/ACBP mRNA levels was abolished in the presence of the protein synthesis inhibitor cycloheximide, implying a role for labile or Androgen-induced proteins in this Androgen stimulation. This is in contrast to the Androgen stimulation of the mRNA encoding prostate-specific antigen (PSA), suggesting that different mechanisms are involved in the Androgen regulation of these two genes. Although further experiments are required to confirm that DBI/ACBP is secreted by prostatic epithelial cells, these data demonstrate that the mRNA encoding DBI/ACBP is expressed in prostate cells and is affected by Androgens in Androgen-responsive LNCaP cells.

Johannes V. Swinnen – 2nd expert on this subject based on the ideXlab platform

  • Androgens stimulate fatty acid synthase in the human prostate cancer cell line LNCaP
    Cancer Research, 1997
    Co-Authors: Johannes V. Swinnen, Murielle Esquenet, Karine Goossens, Walter Heyns, Guido Verhoeven

    Abstract:

    In addition to modulation of cell proliferation and stimulation of prostate-specific antigen secretion, one of the most striking effects of Androgens on the human prostate cancer cell line LNCaP is the accumulation of neutral lipids. These lipids are synthesized de novo, suggesting that LNCaP cells express all enzymes required for endogenous lipogenesis and that the expression and/or activity of some of these enzymes is affected by Androgens. One of the key enzymes involved in lipogenesis is fatty acid synthase (FAS), a potential prognostic enzyme and therapeutic target that is found to be frequently overexpressed in a variety of cancers including prostate cancer. Here, using Northern blot analysis, the gene encoding FAS is shown to be abundantly expressed in LNCaP cells and in two other prostate cancer cell lines tested (PC-3 and DU-145). In LNCaP cells, Androgen treatment (10(-8) M R1881) causes a 3-4-fold increase in FAS mRNA levels. Concomitantly with the increase in FAS gene expression, Androgens induce a 10-12-fold stimulation of FAS activity. Effects are dose- and time-dependent and follow courses similar to those of the Androgen induction of lipid accumulation. In support of the involvement of the Androgen receptor, steroid specificity of regulation of FAS activity is in agreement with the aberrant ligand specificity of the mutated Androgen receptor in LNCaP cells. Stimulation of FAS activity is inhibited by the antiAndrogen Casodex (bicalutamide) and is absent in the Androgen receptor-negative cell lines PC-3 and DU-145. Taken together, these data demonstrate that Androgens, mediated by the Androgen receptor, stimulate the expression and activity of FAS and suggest that stimulation of FAS activity represents at least part of the mechanism by which Androgens induce the accumulation of neutral lipids in LNCaP cells.

  • Androgens markedly stimulate the accumulation of neutral lipids in the human prostatic adenocarcinoma cell line lncap
    Endocrinology, 1996
    Co-Authors: Johannes V. Swinnen, Murielle Esquenet, Walter Heyns, P P Van Veldhoven, Guido Verhoeven

    Abstract:

    Microscopic evaluation of LNCaP cells stained with the lipophilic dye Oil red O revealed that Androgens induce a marked stimulation of lipid droplet accumulation. As determined by quantitative analysis of the Oil red O extracted from the stained cells, stimulatory effects of the synthetic Androgen R1881 became apparent at concentrations as low as 10(-11) M. Maximal induction (15-fold) was reached at 10(-8) M. Increases were observed 2 days after hormone addition and were maximal 1 day later. Accumulation of lipid droplets was also induced by mibolerone (another synthetic Androgen) and by the natural Androgens testosterone and dihydrotestosterone. In agreement with the aberrant ligand specificity of the mutated Androgen receptor in LNCaP cells, stimulation of lipid accumulation was also apparent after treatment with progesterone and estradiol. Cortisol and the synthetic glucocorticoid dexamethasone were ineffective. The Androgen antagonist Casodex (bicalutamide) abolished the stimulatory effect of R1881, f…

  • Androgen regulation of the messenger rna encoding diazepam binding inhibitor acyl coa binding protein in the human prostatic adenocarcinoma cell line lncap
    Molecular and Cellular Endocrinology, 1994
    Co-Authors: Johannes V. Swinnen, Murielle Esquenet, Walter Heyns, Wilfried Rombauts, Guido Verhoeven

    Abstract:

    Abstract To study the mechanisms by which Androgens intervene in the regulation of growth and differentiation of human prostatic epithelial cells, cDNA clones encoding putative prostate-secreted proteins were characterized and tested as potential markers for Androgen action. One of the isolated cDNAs expressed diazepam-binding inhibitor/acyl-CoA-binding protein (DBI/ACBP), suggesting that this polypeptide, that has been implicated in a large number of biochemical processes, is expressed and secreted by prostate cells. As demonstrated by Northern blot analysis, the mRNA encoding DBI/ACBP was expressed in prostate tissue and in the three human prostatic adenocarcinoma cell lines tested: LNCaP, PC-3 and DU-145. In Androgen-sensitive LNCaP cells, the synthetic Androgen R1881 stimulated the DBI/ACBP steady state mRNA levels with half maximal effects at a concentration of 0.2 nM. Increases were a maximal 12 h after addition of the synthetic hormone. DBI/ACBP mRNA levels could also be stimulated by the synthetic Androgen mibolerone and by the natural Androgens testosterone and dihydrotestosterone. In agreement with the altered steroid specificity of the Androgen receptor in LNCaP cells, estradiol and progesterone also exerted a stimulatory effect. Cortisol and the synthetic glucocorticoid dexamethasone were without effect. Androgen stimulation of DBI/ACBP mRNA levels was abolished in the presence of the protein synthesis inhibitor cycloheximide, implying a role for labile or Androgen-induced proteins in this Androgen stimulation. This is in contrast to the Androgen stimulation of the mRNA encoding prostate-specific antigen (PSA), suggesting that different mechanisms are involved in the Androgen regulation of these two genes. Although further experiments are required to confirm that DBI/ACBP is secreted by prostatic epithelial cells, these data demonstrate that the mRNA encoding DBI/ACBP is expressed in prostate cells and is affected by Androgens in Androgen-responsive LNCaP cells.

E Mulder – 3rd expert on this subject based on the ideXlab platform

  • effect of culture conditions on Androgen sensitivity of the human prostatic cancer cell line lncap
    The Prostate, 1993
    Co-Authors: Erna G Langeler, Connie J C Van Uffelen, Marinus A Blankenstein, Gert J Van Steenbrugge, E Mulder

    Abstract:

    Several effects of Androgens on LNCaP-FGC prostate tumor cells showed a biphasic pattern. Stimulation of growth and inhibition of secretion of prostatic acid phosphatase (PAP) was observed at low Androgen concentrations (below 1 nM of the synthetic Androgen R1881), and inhibition of growth and stimulation of PAP secretion was observed at higher concentrations. In contrast, prostate specific antigen (PSA) secretion did not show this biphasic response pattern. Comparable effects were found for two sublines of the LNCaPFGC cells: an early (passage 20, Androgen-dependent) and relatively late (passage 70, Androgen-sensitive) passage of the cells. Culturing of both sublines in the presence of a high concentration of Androgens (10 nM R1881) resulted initially in a decrease in growth rate, but the cells started to proliferate within 3 weeks. These cells became less sensitive to Androgens, lost their biphasic response pattern, and showed reduced Androgen receptor levels. Three weeks after removal of the excess of Androgens, the passage 70 cells regained a biphasic growth response to Androgens. Culture in medium without steroids but with EGF resulted in a decrease of both Androgen sensitivity and Androgen receptor level. In conclusion, rapid changes of the Androgen sensitivity and receptor level of the LNCaP cells occurred under the influence of culture conditions. These changes were partly reversible and, therefore, were most likely due to adaptation of the cells.

  • the Androgen receptor in lncap cells contains a mutation in the ligand binding domain which affects steroid binding characteristics and response to antiAndrogens
    The Journal of Steroid Biochemistry and Molecular Biology, 1992
    Co-Authors: Jos Veldscholte, Cor A Berrevoets, Carrie Risstalpers, George G J M Kuiper, Guido Jenster, Jan Trapman, A O Brinkmann, E Mulder

    Abstract:

    Abstract The human prostate tumor cell line LNCaP containd an abnormal Androgen receptor system with broad steroid binding specificity. Progestagens, estradiol and several antiAndrogens compete with Androgens for binding to the Androgen receptor in the cells to a higher extent than in other Androgen sensitive systems. Optimal growth of LNCaP cells is observed after addition of the synthetic Androgen R1881 (0.1 nM). In addition, estrogens, progestagens and several antiAndrogens do not inhibit Androgen responsive growth, but have striking growth stimulatory effects and increase EGF receptor level and acid phosphatase secretion. We have found that the Androgen receptor in the LNCaP cells contains a single point mutation changing the sense of codon 868 (Thr to Ala) in the ligand binding domain. Expression vectors containing the normal or mutated Androgen receptor sequence were transfected into COS or HeLa cells. Androgens, progestagens, estrogens and several antiAndrogens bind the mutated Androgen receptor proteon and activate the expression of an Androgen-regulated reporter gene (GRE-tk-CAT), indicating that the mutation directly affects both binding specificity and the induction of gene expression. Interestingly, the antiAndrogen casodex showed antiAndrogenic properties in growth studies of LNCaP cells and did not induced reporter gene activity in Hela cells transfected with the mutant receptor. The mutated Androgen receptor of LNCaP cells is therefore a useful tool in the elucidation of different levels of action of steroids and antisteroids.

  • a mutation in the ligand binding domain of the Androgen receptor of human lncap cells affects steroid binding characteristics and response to anti Androgens
    Biochemical and Biophysical Research Communications, 1990
    Co-Authors: Jos Veldscholte, Cor A Berrevoets, Carrie Risstalpers, George G J M Kuiper, Guido Jenster, Jan Trapman, A O Brinkmann, Eric Claassen, H C J Van Rooij, E Mulder

    Abstract:

    LNCaP prostate tumor cells contain an abnormal Androgen receptor system. Progestagens, estradiol and anti-Androgens can compete with Androgens for binding to the Androgen receptor and can stimulate both cell growth and excretion of prostate specific acid phosphatase. We have discovered in the LNCaP Androgen receptor a single point mutation changing the sense of codon 868 (Thr to Ala) in the ligand binding domain. Expression vectors containing the normal or mutated Androgen receptor sequence were transfected into COS or Hela cells. Androgens, progestagens, estrogens and anti-Androgens bind the mutated Androgen receptor protein and activate the expression of an Androgen-regulated reporter gene construct (GRE-tk-CAT). The mutation therefore influences both binding and the induction of gene expression by different steroids and antisteroids