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PubMed1992

Cloning and characterization of an androgen-induced growth factor essential for the androgen-dependent growth of mouse mammary carcinoma cells.

An androgen-dependent mouse mammary carcinoma cell line (SC-3) requires androgen for growth stimulation. We have shown previously that androgen acts on SC-3 cells to induce secretion of a fibroblast growth factor (FGF)-like growth factor, which in turn stimulates growth of the cells in an autocrine manner. In this study, the androgen-induced growth factor (AIGF) was purified from a conditioned medium of SC-3 cells stimulated with testosterone. cDNA cloning of AIGF by use of its partial amino acid sequence data revealed that AIGF is a distinctive FGF-like growth factor. An AIGF cDNA (pSC17) encodes a 215-amino acid protein with a putative signal peptide, which shares 30-40% homology with known members of the FGF family. The AIGF mRNA was markedly induced by 10 nM testosterone in Northern blot analysis. Expression of AIGF cDNA in mammalian cells clearly showed remarkable stimulatory effects of AIGF on growth of SC-3 cells in the absence of androgen. Thus, it is clear that the androgen-induced growth of SC-3 cells is mediated in an autocrine manner by AIGF, which is secreted by the tumor cells themselves in response to hormonal stimuli.

Amino Acid Sequence↗
PubMed1995

Effects of gonadal androgens and oestrogens on adrenal androgen levels.

OBJECTIVE: The physiological role of adrenal androgens in humans remains unclear. Furthermore, there are few data on the relation between sex steroids and adrenal androgen production. We have assessed the effects of sex steroid hormone administration on adrenal androgen levels, by studying a large group of transsexual patients. DESIGN: A non-randomized intervention. SETTING: A university teaching hospital. PATIENTS: Thirty-one male-to-female and 22 female-to-male transsexual patients. MEASUREMENTS: Plasma levels of adrenal androgens were measured in a group of male-to-female and female-to-male transsexual patients both before and during cross-gender hormone treatment. This treatment involves administration of testosterone esters to women and of ethinyloestradiol and cyproterone acetate to men. RESULTS: High dose sex steroid administration had marked effects on adrenal androgens levels, which decreased by 27-48% in males treated with ethinyloestradiol and increased by 23-70% in females treated with testosterone. CONCLUSION: We conclude that administration of high doses of testosterone and oestradiol exert opposing effects on adrenal androgen production.

Adolescent↗
PubMed2005

Increased Hsp27 after androgen ablation facilitates androgen-independent progression in prostate cancer via signal transducers and activators of transcription 3-mediated suppression of apoptosis.

One strategy to improve therapies in prostate cancer involves targeting cytoprotective genes activated by androgen withdrawal to delay the emergence of the androgen-independent (AI) phenotype. The objectives of this study were to define changes in Hsp27 levels after androgen ablation and to evaluate the functional relevance of these changes in AI progression. Using a tissue microarray of 232 specimens of hormone-naïve and post-hormone ablation-treated prostate cancer, we found that Hsp27 levels increase after androgen ablation to become highly expressed (>4-fold, P < or = 0.01) in AI tumors. Hsp27 overexpression rendered LNCaP cells highly resistant to androgen withdrawal both in vitro and in vivo. Tumor volume and serum prostate-specific antigen levels increased 4.3- and 10-fold faster after castration when Hsp27 was overexpressed. Treatment of LNCaP tumor cells in vitro with Hsp27 antisense oligonucleotides (ASO) or short-interfering RNA suppressed Hsp27 levels in a dose-dependent and sequence-specific manner increased the apoptotic sub-G0-G1 fraction and caspase-3 cleavage >2-fold, as well as decreased signal transducers and activators of transcription 3 (Stat3) levels and its downstream genes, c-fos and sPLA-2. The cytoprotection afforded by Hsp27 overexpression was attenuated by Stat3 knockdown using specific Stat3 ASO. Coimmunoprecipitation and immunofluorescence confirmed that Hsp27 interacts with Stat3 and that Stat3 levels correlated directly with Hsp27 levels. Hsp27 ASO treatment in athymic mice bearing LNCaP tumors significantly delayed LNCaP tumor growth after castration, decreasing mean tumor volume and serum prostate-specific antigen levels by 57% and 69%, respectively. These findings identify Hsp27 as a modulator of Stat3-regulated apoptosis after androgen ablation and as a potential therapeutic target in advanced prostate cancer.

Animals↗
PubMed2005

Androgen receptor signaling is required for androgen-sensitive human prostate cancer cell proliferation and survival.

BACKGROUND: Androgens and androgen receptors (AR) regulate normal prostate development and growth. They also are involved in pathological development of prostatic diseases, including benign prostatic hyperplasia (BPH) and prostate cancer (PCa). Antiandrogen therapy for PCa, in conjunction with chemical or surgical castration, offers initial positive responses and leads to massive prostate cell death. However, cancer cells later appear as androgen-independent PCa. To investigate the role of AR in prostate cell proliferation and survival, we introduced a vector-based small interfering RNA (siRNA). This siRNA targeted 5'-untranslated region of AR mRNA for extended suppression of AR expression in androgen-sensitive human prostate LNCaP cells. RESULTS: The siRNA design successfully suppressed endogenous AR expression, as revealed by western blotting and immunofluorescence staining in LNCaP cells. LNCaP cells did not proliferate in the absence of AR and underwent apoptosis, based on elevated phospho-Histone H2B expression and higher number of apoptotic body as compared to control cells. CONCLUSION: We demonstrated that AR is vital for prostate cell proliferation and survival in this androgen-sensitive prostate cell line. These results further strengthen the hypothesis that AR can be a therapeutic target for treating androgen-sensitive stages of PCa. Unlike antiandorgens, however, siRNA targeting AR provides a direct inactivation of AR function through the suppression of AR protein expression.

Journal Article↗
PubMed1990

Interaction of androgen-induced autocrine heparin-binding growth factor with fibroblast growth factor receptor on androgen-dependent Shionogi carcinoma 115 cells.

Stimulation of a Shionogi carcinoma 115-derived cultured cell line (SC-3) with androgen resulted in secretion of heparin-binding growth factor. In this study, we analyzed cell-surfaced receptors for growth factors. Binding data of growth factors on intact SC-3 cells revealed the presence of low and high affinity receptors for epidermal growth factor (EGF), insulin, and fibroblast growth factor (FGF). The dissociation constant values were 50 pM and 1.0 nM for EGF, 1.2 nM and 30 nM for insulin, and 34 pM and 7.5 nM for FGF. The numbers of maximal binding sites were 300 and 900/cell for EGF, 2,000 and 14,000/cell for insulin, and 13,000 and 810,000/cell for FGF. To examine the association of androgen-induced growth factor with one of these receptors, the conditioned medium prepared from androgen-stimulated SC-3 cells was fractionated through a heparin-Sepharose column. Growth factor activity adsorbed and eluted by 1 M NaCl from the column was comigrated with the activity inhibiting FGF-receptor association. In addition, basic 125I-FGF was cross-linked, using disuccinimidyl suberate, to the receptor with an apparent molecular weight of 130,000, whose labeling was inhibited when basic FGF, acidic FGF, or highly purified androgen-induced growth factor was present in excess. Furthermore, the highly purified growth factor-, basic FGF- or androgen-induced growth of SC-3 cells was significantly and similarly inhibited by anti-basic FGF antibody IgG. These results indicate that androgen-induced FGF-like factor acts as an autocrine growth factor via the FGF receptor in a process of SC-3 cell proliferation.

Animals↗
PubMed1991

Amber mutation creates a diagnostic MaeI site in the androgen receptor gene of a family with complete androgen insensitivity.

We have discovered in the X-linked androgen receptor gene a single nucleotide substitution that is the putative cause of complete androgen insensitivity (resistance) in a family with affected individuals in 2 generations. Earlier studies on the family indicated co-segregation of mutant phenotype and the RFLPs at the loci DXS1 and DXYS1. The mutation is an adenine-to-thymine transversion in exon 8 that changes the sense of codon 882 from lysine to an amber (UAG) translation termination signal. The substitution creates a recognition sequence for the restriction endonuclease MaeI: this permits ready recognition of hemizygotes and heterozygotes after amplification of genomic exon 8 by the polymerase chain reaction. The mutation predicts the synthesis of a truncated receptor that lacks 36 amino acids at the carboxy terminus of its 252-amino acid androgen-binding domain. The cultured genital skin fibroblasts of the one affected patient examined have normal levels of androgen receptor mRNA, but negligible androgen-receptor binding activity. These results accord with a variety of data from spontaneous and artificial mutations indicating that all portions of the steroid binding domain contribute to normal steroid binding by a steroid receptor.

Amino Acid Sequence↗
PubMed2004

EGF receptor (EGFR) signaling promoting invasion is disrupted in androgen-sensitive prostate cancer cells by an interaction between EGFR and androgen receptor (AR).

We previously demonstrated that expression of androgen receptor (AR) by transfection of the androgen-independent prostate cancer cell line PC3 decreases invasion and adhesion of these cells (PC3-AR) through modulation of alpha6beta4 integrin expression. The treatment with androgens further reduced invasion of the cells without modifying alpha6beta4 expression, suggesting an interference with the invasion process by androgens. Here, we investigated EGF-mediated signal transduction processes that lead to invasion in PC3-AR cells. We show that EGF-induced EGFR autotransphosphorylation is reduced in PC3-AR cells compared to PC3 cells transfected only with the vector (PC3-Neo). EGF-stimulated PI3K activity, a key signaling pathway for invasion of these cells, and EGF-PI3K interaction are also decreased in PC3-AR cells and further reduced by treatment with androgen. Finally, we show that EGFR internalization process was reduced in PC3-AR and LNCaP cells compared to PC3-Neo. Investigations on the location of AR in PC3-AR transfected cells were also conducted. Immunoconfocal microscopy and coimminoprecipitation studies demonstrated the presence of an interaction between EGFR and AR at membrane level in PC3-AR and LNCaP cells. In conclusion, our results suggest that the expression of AR by transfection in PC3 cells confers a less-malignant phenotype by interfering with EGFR signaling leading to invasion through a mechanism involving an interaction between AR and EGFR.

Androgens↗
PubMed2006

Direct activation of TGF-beta1 transcription by androgen and androgen receptor complex in Huh7 human hepatoma cells and its tumor in nude mice.

Importance of androgen for promotion of hepatocelullar carcinoma (HCC) has long been supported by clinical and experimental evidences. However, mechanisms involved in the carcinogenesis have not yet been fully elucidated. Moreover, unbalanced expression of TGF-beta1 during tumor progression results in prooncogenic rather than growth inhibition. To investigate the effect of androgen on transcriptional regulation of TGF-beta1, we isolated rat TGF-beta1 promoter, based on our previous report (GenBank AF249327), and examined regulation of its promoter activity by dihydrotestosterone in Huh7, LNCaP, and PC3 cells. Several putative transcription factor-binding sites were found, but no TATA box. When the full-length (-4784 to +68) and variously deleted promoter DNAs were evaluated, the promoter region spanning from -2732 to -1203 showed the highest activity towards dihydrotestosterone in a dose-dependent manner in both Huh7 and PC3 cells with androgen receptor (AR) expression. Putative androgen response sequence half site (5'-TGTCCT-3') was identified to be located within -1932 to -1927, proved by mutant (5'-AGACCT-3') analysis and chromatin immunoprecipitation (ChIP) assay. AR mediated upregulation of TGF-beta1 expression was confirmed by HCC developed in nude mice with AR-overexpressed Huh7-cells. This work presents in vivo and in vitro evidences of activation of TGF-beta1 expression by androgen and AR, and implicates the modulation of hepatocarcinogenesis by AR through the regulation of TGF-beta1 expression.

Androgens↗
PubMed1994

Androgen receptor in the harderian glands of the golden hamster: characterization and the effects of androgen deprivation, the pituitary, and gender.

The harderian glands of the golden hamster were found, by a competitive binding assay using [3H]mibolerone as the ligand, to have a high affinity androgen receptor. In intact male hamsters, this receptor was present in both cytosolic and nuclear KCl-extractable fractions. Castration or hypophysectomy led to 3- to 5-fold increases in the concentrations of cytosolic receptor with decreased dissociation constants. Hypophysectomy with maintenance of prolactin levels (by removal of pituitaries and their implantation either in the sella turcica or under the kidney capsule) had no effect on androgen receptor binding, compared to hypophysectomy alone. Female hamsters had androgen receptor levels which were 2 to 4 times higher than those of intact males. Hypophysectomy led to elevated receptor binding in ovariectomized female hamsters and this rise was prevented by maintaining prolactin levels. Binding of [3H]mibolerone in male glands was effectively inhibited by 5 alpha-dihydrotestosterone, whereas the parent molecule, testosterone, required approximately a 10-fold greater molar excess to achieve the same amount of inhibition. Estradiol and progesterone were relatively poor inhibitors of the observed binding of [3H]mibolerone, while dexamethasone was ineffective. Sucrose gradient studies indicated that the harderian androgen receptor migrated to the 8S region, as expected for this receptor in molybdate-containing gradients. These results indicate that the androgen receptor in the hamster harderian gland is a 5 alpha-dihydrotestosterone receptor.

Androgens↗
PubMed2001

Androgen receptor expression in androgen-independent prostate cancer cell lines.

BACKGROUND: Almost all attempts at establishing prostate carcinoma cell lines have resulted in generation of cells that are androgen-independent, including commonly used LNCaP which expresses androgen receptor (AR) and AR-negative Du145 and PC-3. We attempted to clarify the mechanism(s) responsible for the failure to respond to androgen. METHODS: Cell lines LNCaP, CWR22R, PC-3, Du145, and CA7T2CL were used to examine the AR promoter function with a reporter gene assay and its methylation status by Southern blot, PCR of bisulfite-converted DNA, and 5-aza-2'-deoxycytidine treatment. Structural abnormalities of the AR were identified by sequencing of reverse-transcribed mRNA. RESULTS: All tested AR-positive prostate carcinoma cells were capable of AR transcription at a significantly higher level than PC-3 and Du145, thus suggesting relative deficiency of the transcription factors in the AR-negative cells, further associated with methylation. Examination of CWR22R cells, which express the AR but are androgen-independent, identified an in-frame duplication of exon 3, which resulted in insertion of 39 amino acids in the DNA-binding domain. CONCLUSIONS: Relative deficiency of transcription factors associated with methylation is responsible for the lack of AR promoter function in most of AR-negative cell lines. Mutations in the AR gene are present in the cells that express the AR but are androgen-independent.

Adenocarcinoma↗
PubMed2005

Effect of GGC (glycine) repeat length polymorphism in the human androgen receptor on androgen action.

BACKGROUND: The human androgen receptor (AR) contains glutamine (CAG) and glycine (GGC) repeat length polymorphisms. Normal glutamine repeat length affects androgen action, but an effect of normal glycine repeat length has not been studied. METHODS: To determine whether glycine/GGC repeat length affects AR function, we constructed AR cDNA expression vectors with different GGC repeat lengths in the physiological range (13-17 GGCs). AR constructs were transfected into AR-negative DU145 human prostate cancer cells along with an androgen-responsive reporter plasmid (PSA-firefly luciferase) and a transfection efficiency control plasmid (Renilla luciferase). RESULTS: Glycine repeat length had no significant effect on androgen-dependent AR transactivation activity expressed as firefly luciferase per unit amount of AR protein. However, AR protein levels (normalized for transfection efficiency) were inversely affected by glycine repeat length (P < 0.001; r = -0.9; e.g., GGC13 yielded 2.7 times more AR protein than did GGC17). Therefore, the net amount of AR activity per cell would be higher in cells expressing AR with a short glycine repeat. Based on programs that predict structure from RNA sequence, the GGC repeat can form a hairpin structure, the free energy of which decreases (i.e., hairpin stability increases) as a function of increasing repeat length. This suggests that hairpin stability may interfere with translation, accounting for the inverse effect of GGC repeat length on AR protein yields. CONCLUSIONS: The ability of a short GGC repeat to enhance androgen action provides a biologically plausible mechanism to account for reports that a short GGC repeat in the AR gene is a risk factor for prostate cancer.

Androgens↗
PubMed1984

Synthesis and evaluation of immobilized androgens for affinity chromatography in the purification of nuclear androgen receptor.

Seven biospecific adsorbents containing immobilized androgens were synthesized: dihydrotestosterone-17 beta-succinyl agarose, and both the unsubstituted and the 17 beta-acetyl derivatives of dihydrotestosterone-7 alpha-undecanoyl agarose, testosterone-7 alpha-undecanoyl agarose, and 19-nortestosterone-7 alpha-undecanoyl agarose. The retention capacities for nuclear androgen receptor were generally between 40-80% with little variation in reproducibility; the amount of binding was greatest with dihydrotestosterone-17 beta-succinyl agarose and dihydrotestosterone-17 beta-acetoxy-7 alpha-undecanoyl agarose. Rapid flow rates were obtained with all gels, and no tendency for decomposition was observed over a period of 1 year. Factors that affected retention included the concentration of immobilized androgen, length of the linker arm, occupation of receptor sites, interval of contact with the gel, and temperature of incubation. Chemical dissociation of androgens from androgen receptor complexes with 0.2 mM mersalyl increased the retention of receptor by dihydrotestosterone-17 beta-succinyl agarose. Two elutants showed promise for the dissociation of gel-bound receptor: 1) 0.2 mM mersalyl in the presence of 1.5 mg/ml of ovalbumin; 2) 10% (v/v) dimethylformamide:water containing 30 microM [1,2-3H] dihydrotestosterone and 0.5 M sodium thiocyanate.

Androgens↗
PubMed1986

Increased recovery of androgen receptors from human prostate through the use of mersalyl: evidence for androgen regulation of the binding sites in carcinomatous prostate.

With a technique adapted for needle biopsies from human prostate, androgen receptors have been quantitated in normal, hyperplastic, and carcinomatous samples. An important improvement in the yield of cytosol specific binding sites was obtained when samples were pre-incubated with the mercurial reagent mersalyl, which dissociates endogenously bound hormone receptor complexes, before the binding assay with 3H-methyltrienolone (3H-R1881). Androgen receptors in normal prostate tissue were found to be highest (7.81 +/- 1.12 pmoles/g tissue), and significantly different from hyperplastic prostate (2.02 +/- 0.55 pmoles/g tissue, p less than 0.025), but not from carcinomatous samples (4.47 +/- 0.79 pmoles/g tissue). Mean values for hyperplastic and carcinoma were not statistically distinguishable (p less than 0.1). The clinical response to hormone therapy in 85% of 13 patients with prostatic adenocarcinoma reflected the prostatic androgen receptor content. Orchidectomy followed by estrogen administration for several months leads to a dramatic fall (8-fold) in total androgen receptors in carcinomatous prostate, while estrogen alone did not seem to produce a significant effect. These preliminary data suggest that androgen could directly regulate its binding sites, as demonstrated earlier for other animal target organs.

Adult↗
PubMed1989

Side gland of Suncus murinus as a new model of sebaceous gland: 5 alpha-reductase, androgen receptor, and nuclear androgen content in male and female animals.

The side gland of Suncus murinus is composed of well-developed sebaceous glands in both males and females. We measured the 5 alpha-reductase activity, androgen receptor content, and the intranuclear concentrations of testosterone and dihydrotestosterone in this side gland taking it as a new experimental model of human sebaceous glands. Lineweaver-Burk plot analysis suggested the presence of two classes of 5 alpha-reductase with different Km for testosterone in the homogenate. The enzyme activity was slightly higher in males than in females in the presence of a high concentration of testosterone. The levels of androgen receptors were approximately 40 and 30 fmol/mg protein in the cytosol and nuclei, respectively. The values did not differ significantly between males and females. The intranuclear concentration of dihydrotestosterone in the side gland was higher than that of testosterone in each sex. The intranuclear level of each of these two androgens in the female side gland was comparable to that in the male side gland despite the fact that the serum level of testosterone was much lower in the female. These data clearly indicate that the side gland is a typical target tissue for androgens in the female as well as in the male. Androgens other than testosterone may serve as precursors of dihydrotestosterone in the female side gland.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1998

Molecular analysis of the androgen receptor gene in 4 patients with complete androgen insensitivity.

Androgen insensitivity syndromes are due to defects in the androgen receptor gene. In this study, we analyzed the androgen receptor gene in four cases with complete androgen insensitivity syndrome. In patient 1, one substitutional mutation [arginine (codon CGC) to cysteine (codon TGC) at position 774] of exon F was identified. This position was located in the hormone binding domain and appeared to be one hot spot of mutations because the mutations at the same position in several unrelated cases were reported before. In patient 2, one substitutional mutation [tyrosine (codon TAT) to cysteine (codon TGT) at position 571] of exon B was identified. This position was located in the DNA binding domain. In patients 3 and 4 (siblings), one substitutional mutation [arginine (codon CGA) to glutamine (codon CAA) at position 752] of exon E was identified. Taken together, these abnormalities might be related to the pathogenesis of complete androgen insensitivity.

Adolescent↗
PubMed2005

Expression of androgen receptor and androgen regulation of NDRG2 in the rat renal collecting duct.

Androgens are known to regulate gene expression in the renal proximal tubule. Whether the distal parts of the nephron, in particular the cortical collecting duct (CCD), where sodium reabsorption is controlled tightly by aldosterone, are also targets for these hormones is unknown. Real-time PCR on rat isolated renal tubules showed that androgen receptor mRNA is not only, as expected, expressed in the proximal tubule, but also in the CCD. We examined the effects of adrenalectomy (ADX) plus castration and in-vivo administration of the active metabolite of testosterone, dihydrotestosterone (DHT), on the intrarenal expression of N-myc downstream regulated gene 2 (NDRG2), an early aldosterone-induced gene located specifically in the CCD. NDRG2 belongs to a newly identified family of differentiation-related genes; although the function of these genes remains elusive, regulation of NDRG1 by androgens has been suggested. Castration plus ADX increased NDRG2 expression (RNase protection assay) significantly in the whole kidney, and a single i.p. injection of DHT caused a significant decrease in NDRG2 expression 4 h afterwards (up to 24 h). Furthermore, real-time PCR on microdissected tubules revealed that the decrease in NDRG2 expression caused by DHT is restricted to the CCD. Thus, aldosterone and androgens have opposite effects on NDRG2 expression in the renal CCD. These results are the first demonstration of androgen-dependent gene regulation in the rat renal CCD.

Adrenalectomy↗
PubMed1998

Functional characterisation of mutations in the ligand-binding domain of the androgen receptor gene in patients with androgen insensitivity syndrome.

Five mutations in the ligand-binding domain of the androgen receptor gene were identified in patients with complete (A765T, C784Y, R831X and M895T) or partial (R840G) androgen insensitivity. A765T and R831X have been reported previously whereas the other three mutations are novel. Receptors carrying these mutations were transiently expressed in COS-1 cells, and androgen binding and capacity to transactivate an androgen-responsive reporter gene were assayed. C784Y led to abolished androgen binding and transactivating capacity, R840G and M895T showed reduced specific binding and partial transactivation. The in vitro functions of the R840G and M895T mutants were improved with supraphysiological concentrations of steroid.

Androgen-Insensitivity Syndrome↗
PubMed1990

Androgen resistance due to decreased amounts of androgen receptor: a reinvestigation.

To provide insight into the pathogenesis of the androgen resistance in a previously described family with X-linked Reifenstein syndrome, we have systematically assessed a variety of parameters of androgen receptor function in fibroblasts cultured from scrotal skin biopsies. We assessed the amount of high affinity binding, the affinity of ligand binding to the receptor, the upregulation of androgen receptor levels by androgen, the stability of ligand binding in intact fibroblasts at high temperature, the dissociation of ligand from the receptor, the intranuclear localization and salt elution profiles of ligand-receptor complexes, and the ultracentrifugation characteristics of the ligand-receptor complexes. Since the only parameter found to be abnormal is a decreased amount of receptor, we conclude that the underlying mutation in this family influences the amount rather than the structure of the androgen receptor protein.

Androgens↗