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PubMed1983

Androgen stimulated elevation in androgen receptor levels is inhibited by the synthetic glucocorticoid triamcinolone acetonide.

Two cloned tumor cell lines derived from the rat prostate and hamster ductus deferens contain receptors for androgens and glucocorticoids. Androgens increase both the rate of proliferation in these cells and induce a doubling in the number of androgen receptors within 6 hours. This elevation in androgen receptors is dependent on protein synthesis. The glucocorticoid triamcinolone acetonide specifically inhibits both these androgen mediated events without altering the equilibrium dissociation constant (Kd) of the androgen receptor for either [3H]-methyltrienolone (Kd = 0.46 nM) or [3H]-dihydrotestosterone (Kd = 0.2 nM). These observations infer that androgen receptor up-regulation is an important facet of androgen action which may be modulated by glucocorticoids.

Androgens↗
PubMed2002

The role of androgens and the androgen receptor in prostate cancer.

Prostate cancer (PCa) is the leading diagnosed malignancy in men in western countries. The relationship between androgens and the androgen receptor (AR) has been studied extensively in PCa. Plasma levels of androgens show variations between different populations, and in many cases this correlates with PCa susceptibility. Indeed, exposure of the fetus to higher androgen concentrations appears to be a risk factor for PCa. The AR is present in the majority of PCa, and its activation by androgens leads to different proliferative, apoptotic and angiogenic events. These events are in turn mediated by dysregulation of cyclin-dependent kinases, apoptotic factors and even mutations in the AR. Although androgen ablation has been the mainstay non-surgical treatment for this disease, most tumors will eventually become refractory to treatment. Different cellular mechanisms appear to be involved in the androgen-independent progression of PCa, including cytokine and growth factor-mediated activation of the AR as well as neuroendocrine differentiation. Thus, an understanding of the cellular mechanisms involved in androgen action may lead to better therapeutic targets for PCa.

Androgens↗
PubMed2006

Regulator of G-protein signaling 2 (RGS2) inhibits androgen-independent activation of androgen receptor in prostate cancer cells.

Hormones acting through G protein-coupled receptors (GPCRs) can cause androgen-independent activation of androgen receptor (AR) in prostate cancer cells. Regulators of G-protein signaling (RGS) proteins, through their GTPase activating protein (GAP) activities, inhibit GPCR-mediated signaling by inactivating G proteins. Here, we identified RGS2 as a gene specifically downregulated in androgen-independent prostate cancer cells. Expression of RGS2, but not other RGS proteins, abolished androgen-independent AR activity in androgen-independent LNCaP cells and CWR22Rv1 cells. In LNCaP cells, RGS2 inhibited G(q)-coupled GPCR signaling. Expression of exogenous wild-type RGS2, but not its GAP-deficient mutant, significantly reduced AR activation by constitutively activated G(q)Q209L mutant whereas silencing endogenous RGS2 by siRNA enhanced G(q)Q209L-stimulated AR activity. RGS2 had no effect on RGS-insensitive G(q)Q209L/G188S-induced AR activation. Furthermore, extracellular signal-regulated kinase 1/2 (ERK1/2) was found to be involved in RGS2-mediated regulation of androgen-independent AR activity. In addition, RGS2 functioned as a growth suppressor for androgen-independent LNCaP cells whereas androgen-sensitive LNCaP cells with RGS2 silencing had a growth advantage under steroid-reduced conditions. Finally, RGS2 expression level was significantly decreased in human prostate tumor specimens. Taken together, our results suggest RGS2 as a novel regulator of AR signaling and its repression may be an important step during prostate tumorigenesis and progression.

Adenocarcinoma↗
PubMed1987

Nuclear and cytosol androgen receptor in androgen dependent dermatoses in female patients.

Determination of cytosol and nuclear androgen receptor (AR) was performed in females with androgen dependent dermatoses. 34 patients with acne, hirsutism and androgenetic alopecia were punch biopsied on day 21 of the menstrual cycle under local anesthesia within correspondent predilection sites. The tissue was snap frozen in liquid nitrogen and stored until receptor assays were performed. Overall evaluation of both, cytosol and/or nuclear AR was positive in 76% of all cases. In 86% of (10 out of 14) females with androgenetic alopecia, in 80% (8 out of 10) of patients with acne and 60% (6 out of 10) of hirsute females cytosol and/or nuclear AR were positive. No significant differences of cytosol androgen receptor levels became evident between the dermatoses. In contrast, nuclear androgen receptor levels showed a trend towards distinct differences with highest levels in hirsutism, followed by androgenetic alopecia and acne. Androgen stimulability thus seems to be superior in the first and minor in the latter. Comparison with previous studies on cytosol androgen receptor in androgen dependent dermatoses shows significantly higher number of positive results by additive nuclear receptor determination. Additional nuclear androgen receptor assay, thus gives a more complete picture of local hormone action.

Acne Vulgaris↗
PubMed1996

The androgen-specific probasin response element 2 interacts differentially with androgen and glucocorticoid receptors.

The nuclear receptors constitute a large family of transcription factors characterized by a well conserved DNA-binding domain. The receptors for glucocorticoids, progestins, mineralocorticoids, and androgens constitute a subgroup because they bind in vitro with high affinity to DNA elements containing a partial palindrome of the core sequence 5'-TGTTCT-3'. In vivo, however, the corresponding steroids differentially regulate the expression of their target genes, even when more than one receptor type is present in a particular cell. The DNA-binding domains of the androgen and of the glucocorticoid receptors bind most androgen response elements with similar relative affinities. In contrast, one element (5'-GGTTCTTGGAGTACT-3') which was recently described in the promoter region of the probasin gene selectively interacts with the DNA-binding domain of the androgen receptor and not with that of the glucocorticoid receptor. From studies with chimeric elements, it can be deduced that it is the left subsequence 5'-GGTTCT-3' which excludes the glucocorticoid receptor domain from binding. In co-transfection experiments where the ARE of the C3(1) gene is responsive to both androgens and glucocorticoids, the probasin element is induced only by androgens and not by glucocorticoids. The existence of response elements which are recognized preferentially by the androgen receptor provides yet another possible mechanism to explain the differences of the in vivo effects between androgens and other steroids of the subgroup.

Androgen-Binding Protein↗
PubMed1992

Molecular defects in the androgen receptor causing androgen resistance.

Patients with androgen resistance exhibit a spectrum of abnormalities of male sexual development ranging from 46,XY phenotypic women (complete testicular feminization) to undervirilized fertile men. The definition of the androgen receptor gene structure has permitted the identification of the defects causing androgen resistance in a number of patients. In some individuals androgen resistance is caused by large-scale structural alterations in the androgen receptor gene. In most patients, however, the androgen receptor mutation is the result of single nucleotide substitutions, which cause premature termination or amino acid replacement that result in the synthesis of defective androgen receptor proteins. These amino acid substitutions identify residues crucial to the normal function of the androgen receptor protein.

Androgens↗
PubMed2007

Suberoylanilide hydroxamic acid (vorinostat) represses androgen receptor expression and acts synergistically with an androgen receptor antagonist to inhibit prostate cancer cell proliferation.

Growth of prostate cancer cells is initially dependent on androgens, and androgen ablation therapy is used to control tumor growth. Unfortunately, resistance to androgen ablation therapy inevitably occurs, and there is an urgent need for better treatments for advanced prostate cancer. Histone deacetylase inhibitors, such as suberoylanilide hydroxamic acid (SAHA; vorinostat), are promising agents for the treatment of a range of malignancies, including prostate cancer. SAHA inhibited growth of the androgen-responsive LNCaP prostate cancer cell line at low micromolar concentrations and induced caspase-dependent apoptosis associated with chromatin condensation, DNA fragmentation, and mitochondrial membrane depolarization at higher concentrations (>/=5 mumol/L). Gene profiling and immunoblot analyses showed a decrease in androgen receptor (AR) mRNA and protein in LNCaP cells cultured with SAHA compared with control cells, with a corresponding decrease in levels of the AR-regulated gene, prostate-specific antigen. Culture of LNCaP cells in steroid-free medium markedly sensitized the cells to SAHA. Moreover, a combination of low, subeffective doses of SAHA and the AR antagonist bicalutamide resulted in a synergistic reduction in cell proliferation and increase in caspase-dependent cell death. Addition of exogenous androgen prevented the induction of cell death, indicating that suppression of androgen signaling was required for synergy. At the subeffective concentrations, these agents had no effect, alone or in combination, on proliferation or death of AR-negative PC-3 prostate cancer cells. Our findings indicate that SAHA is effective in targeting the AR signaling axis and that androgen deprivation sensitizes prostate cancer cells to SAHA. Consequently, combinatorial treatments that target different components of the AR pathway may afford a more effective strategy to control the growth of prostate cancer cells.

Androgen Receptor Antagonists↗
PubMed1988

Mediation by the androgen receptor of the stimulatory and antiandrogenic actions of 17 beta-estradiol on the growth of androgen-sensitive Shionogi mammary carcinoma cells in culture.

Increasing concentrations of 17 beta-estradiol (E2) led to a maximal 7-fold stimulation of growth of the highly androgen-sensitive clone (SEM-1) of the mammary carcinoma Shionogi cell line. Half-maximal stimulation by the estrogen was observed at 100 nM E2. Diethylstilbestrol (DES), on the other hand, a synthetic estrogen with no affinity for the androgen receptor, had no significant stimulatory effect on cell growth but caused growth inhibition at concentrations above 1 microM. Mediation of the action of E2 by the androgen receptor is indicated by the absence of interference of E2 action by the antiestrogen LY156758 while the antiandrogen hydroxyflutamide (3 microM) caused a 50% inhibition of E2 action. While increasing concentrations of E2 led to a progressive increase in cell growth, a progressive shift in the ED50 value of action of dihydrotestosterone (DHT) was observed at intermediate (10-100 nM) concentrations of E2 while 10 microM E2 completely inhibited DHT action. At those high E2 concentrations, however, E2 itself led to a stimulation of cell growth equivalent to approximately 50% of the maximal value achieved by DHT. E2 competed with the specific uptake of [3H]testosterone in intact cells at an inhibition constant (Ki) value of 15 nM, thus indicating direct interaction of E2 with the androgen receptor. Preincubation with E2 had no influence on the apparent affinity of testosterone for the androgen receptor nor on the number of androgen binding sites. The present data demonstrate that both the stimulatory and antiandrogenic action of E2 on the growth of the androgen-sensitive mammary carcinoma cell line SEM-1 are mediated through direct interaction of the estrogen with the androgen receptor. Such data may offer an explanation for the subjective improvements reported in prostate cancer patients receiving a high dose of E2 when relapsing after castration.

Androgen Antagonists↗
PubMed2001

The androgen receptor (AR) amino-terminus imposes androgen-specific regulation of AR gene expression via an exonic enhancer.

Androgen and glucocorticoid receptor (AR, GR), two closely related members of the nuclear receptor superfamily, can recognize a similar cis-acting DNA sequence, or hormone response element (HRE). Despite this apparent commonality, these receptors regulate distinct target genes in vivo. The AR gene itself is regulated by AR but not GR in a variety of cell types, including osteoblast-like cells, as shown here. To understand this specificity, we first identified the DNA sequences responsible for androgen-mediated up-regulation of AR messenger RNA. A 6.5-kb region encompassing exon D, intron 4, and exon E of the AR gene contains four exonic HREs and exhibits cell type-specific, AR-mediated transcriptional enhancement when placed upstream of a heterologous promoter and reporter gene. A 350-bp fragment consisting of just exons D and E exhibits the same cell- and androgen-specificity as the 6.5-kb region, as well as the native AR gene. Consistent with a role for the exonic HREs, androgen regulation via this intragenic enhancer requires the HREs as well as a functional receptor DNA binding domain. A panel of AR/GR chimeric receptors was used to test which AR domains (amino-terminal, DNA binding or ligand binding) confer androgen-specific regulation of the 350-bp enhancer. Only chimeric receptors containing the amino-terminus of AR induced reporter gene activity from the AR gene enhancer. Further, a constitutively active AR consisting of only the AR amino-terminus and DNA binding domain (AA phi) retained the capacity to activate the internal responsive region, unlike a constitutively active chimera harboring the GR amino-terminus and AR DNA binding domain (GA phi). Thus, the AR amino terminus is the sole determinant for androgen-specific regulation of the AR gene internal enhancer. These findings support a model in which the amino termini of ARs bound to HREs within the AR gene interact with an exclusive auxiliary factor(s) to elicit androgen-specific regulation of AR messenger RNA. This is the first example of androgen-specific response in which the necessary and sufficient distinguishing capacity resides within the AR amino terminus.

Androgens↗
PubMed2004

A bioinformatics-based functional analysis shows that the specifically androgen-regulated gene SARG contains an active direct repeat androgen response element in the first intron.

We characterized the specifically androgen-regulated gene (SARG), which is expressed in the androgen receptor (AR) and glucocorticoid receptor (GR) positive cell line lymph node carcinoma of the prostate-1F5 (LNCaP-1F5). SARG mRNA expression can be up-regulated by androgens, but not by glucocorticoids. SARG mRNA expression is high in prostate tissue. SARG is composed of four exons and spans a region of 14.5 kbp on chromosome 1q32.2. Transcripts of 5.5, 3.3 and 2.3 kb are the result of alternative polyadenylation. SARG mRNA splice variants lack exon 2 and vary in length of exon 1. The SARG protein has a length of 601 amino acids and is located in the cytoplasm. By screening the 18 kbp genomic sequence flanking the transcription start site we identified the imperfect direct repeat 5'-TGTGCTaacTGTTCT-3'in intron 1 as an active androgen response element (ARE-SARG+4.6). A 569 bp genomic DNA fragment containing this element functioned as an androgen-specific enhancer in transiently transfected LNCaP-1F5 cells. ARE-SARG+4.6 cooperated with flanking sequences for optimal activity. Inactivation of ARE-SARG+4.6 completely abolished the androgen response of the enhancer. Chromatin immunoprecipitation (ChIP) experiments showed chromatin structural changes of the enhancer in the presence of R1881. ARE-SARG+4.6 was able to bind to the androgen receptor, but not to the glucocorticoid receptor, correlating with its androgen-specific activity in transfections.

Alternative Splicing↗
PubMed2005

Decoy androgen-responsive element DNA can inhibit androgen receptor transactivation of the PSA promoter gene.

Chemotherapy, hormonal therapy, or surgery may cause devastating toxic or other side effects. Androgen receptors (ARs) in the cytoplasm are activated by binding with androgen. Androgen-activated ARs bind to a specific genomic DNA sequence, the androgen-responsive element (ARE), and initiate gene expression at the transcriptional level. Even without androgen activation, ARs may have a role in androgen-refractory prostate cancer. Thus, inhibition of AR activity may have therapeutic value. We applied a genetic reporter of the Dual-Luciferase Assay System to test whether a short double-stranded genomic DNA containing prostate-specific antigen (PSA) ARE sequence as decoy DNA would inhibit the function of activated AR. A 21-mer phosphorothioated PSA ARE decoy DNA was synthesized, with a plasmid vector containing the PSA promoter upstream from a luciferase gene, the reporter gene. The promoter and reporter were co-transfected into a human prostate cancer cell line PC3-M with the aid of Lipofectamin 2000. After 24 hr exposure to androgens, the cells were lysed and luciferase activity measured to determine the ARE decoy inhibitory effect on the function of ARs. Luciferase activity was reduced significantly in the ARE decoy transfected cells but not with inactive control decoy. The results demonstrate that ARE decoy DNA can effectively suppress androgen-activated ARs in prostate cancer cells and indicate the potential utility of decoy DNA for developing a novel therapy for prostate cancer.

Androgen Receptor Antagonists↗
PubMed1991

Peripheral androgen blockade versus glandular androgen suppression in the treatment of hirsutism.

Hirsutism in women is often explained on the basis of abnormal peripheral androgen metabolism. To determine whether serum markers of ovarian, adrenal, or peripheral androgen production may be helpful determinants in the treatment of hirsutism and to compare the efficacy of treatment with dexamethasone or spironolactone, 20 hyperandrogenic hirsute patients were treated for up to 2 years. Eleven women who were selected on the basis of sensitivity to dexamethasone were treated with a daily dose of 0.37 mg dexamethasone and had androgen levels suppressed into the normal range. Although significant (P less than .05), Ferriman-Gallwey scores decreased only by 20%: 14.2 +/- 0.5 to 11.4 +/- 0.6. Nine other women received spironolactone 100 mg/day for 1 year and did not have significant changes in serum androgens, but had a significant (P less than .01) 47% reduction in the Ferriman-Gallwey score (15.2 +/- 0.8 to 8 +/- 0.8). Thus, with either treatment, the reduction in Ferriman-Gallwey scores did not correlate with the change in androgen levels. The patients treated with dexamethasone for 1 year then received spironolactone 100 mg/day together with dexamethasone for an additional year. Serum androgen levels did not change further, but the Ferriman-Gallwey scores decreased significantly (P less than .01) from 11.4 +/- 0.6 to 3.74 +/- 0.7 (-61%). These data suggest that serum androgens are not helpful in assessing response to the treatment of hirsutism and that despite normal androgen levels, only modest clinical improvement may be expected with dexamethasone treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed2006

Risk of the "androgen deprivation syndrome" in men receiving androgen deprivation for prostate cancer.

BACKGROUND: Androgen deprivation therapy for prostate cancer has been associated with a spectrum of adverse effects, such as depression, memory difficulties, and fatigue, termed the androgen deprivation syndrome. Primary care physicians providing follow-up care for men with prostate cancer will be faced with managing these effects. We therefore sought to estimate the incidence of these effects and, by using a control group, ascertain whether these effects were related to androgen deprivation itself. METHODS: We assessed the risk of physician diagnoses of depression, cognitive impairment, or constitutional symptoms in Medicare data following androgen deprivation using a sample of 50 613 men with incident prostate cancer and 50 476 men without cancer, from 1992 through 1997, in the linked Surveillance, Epidemiology, and End Results-Medicare database. Cox proportional hazards regression was used to adjust for confounding variables. RESULTS: Of men surviving at least 5 years after diagnosis, 31.3% of those receiving androgen deprivation developed at least 1 depressive, cognitive, or constitutional diagnosis compared with 23.7% in those who did not (P<.001). After adjustment for variables such as comorbidity, tumor characteristics, and age, the risks associated with androgen deprivation were substantially reduced or abolished: relative risk (RR) for depression diagnosis, 1.08 (95% confidence interval [CI], 1.02-1.15); RR for cognitive impairment, 0.99 (95% CI, 0.94-1.04); and RR for constitutional symptoms, 1.17 (95% CI, 1.13-1.22). CONCLUSION: Depressive, cognitive, and constitutional disorders occur more commonly in patients receiving androgen deprivation, but this appears to be primarily because patients receiving androgen deprivation are older and have more comorbid conditions and more advanced cancers.

Aged↗
PubMed2001

Purification of activins from androgen-independent Shionogi carcinoma cells demonstrates enhanced expression of activin betaB-subunit under androgen-depleted cell conditions in vitro and in vivo.

Here, we report characterization of growth factors secreted from androgen-independent mouse mammary Shionogi carcinoma cells. Previous isolation of fibroblast growth factor 8 (FGF8) from androgen-dependent Shionogi carcinoma SC-3 cells prompted us to characterize growth factors secreted from the androgen-independent cells. After several purification procedures, mitogens for NIH3T3 cells from the androgen-independent cells were identified as activins on the grounds that activin betaA- and betaB-subunits are detected in the active fractions by Western blotting and that the growth-promoting effects by the active fractions are specifically inhibited in the presence of follistatin. In addition, exogenous activins, but not inhibin, stimulated the growth of NIH3T3 cells in a dose-dependent manner. Interestingly, transcripts of activin betaB-subunit were predominantly found in the androgen-independent cells while its betaA-subunit was universally expressed in both androgen-dependent and -independent Shionogi carcinoma cells. In concordant with this in vitro finding, transcripts of activin betaB-subunit were enhanced in murine prostates after castration. Therefore, expression of activin betaB-subunit, but not its betaA-subunit, is likely to be related with androgen-depleted cell conditions in prostates, and possibly in androgen-related cancers.

3T3 Cells↗
PubMed1990

Evidence for androgen receptors in sexually dimorphic perineal muscles of neonatal male rats. Absence of androgen accumulation by the perineal motoneurons.

During development, survival of the sexually dimorphic spinal nucleus of the bulbocavernosus (SNB) and its target perineal muscles, the bulbocavernosus (BC) and the levator ani (LA) is androgen-dependent. To define androgen's site of action in masculinizing SNB system structures, we examined whether or not androgen receptors are present in SNB motoneurons and/or BC/LA muscles of neonatal male rats. Using a receptor binding assay, we have identified androgen-binding factors in the neonatal BC/LA (Bmax = 13.5 fmol/mg protein; Kd = 4.69 nM) for the first time. In contrast, androgen autoradiography provided no evidence that neonatal spinal motoneurons accumulate androgens. These results support the hypothesis that BC/LA muscles are a primary site of androgen action for masculinizing SNB system structures, and that androgen need not interact with SNB motoneurons directly to sexually differentiate them.

Aging↗
PubMed1984

Fluorescent androgen derivatives do not discriminate between androgen receptor-positive and -negative human tumor cell lines.

For the evaluation of histochemical procedures for detection of androgen receptors, three human tumor cell lines have been used: PC-93 and NHIK-3025, both biochemically characterized as androgen receptor-positive, and EB-33, biochemically characterized as androgen receptor-negative. The binding of three fluorescent ligands, testosterone-17 beta-hemisuccinate-bovine serum albumin-fluorescein isothiocyanate, testosterone-17 beta-hemisuccinate-fluoresceinamine, and 5 alpha-dihydrotestosterone-17 beta-hemisuccinate-fluoresceinamine, to the cells was evaluated. The relative binding affinities of the ligands for the androgen receptors were low (less than 5% when compared to methyltrienolone). Treatment of the cells with the androgen-fluoresceinamine derivatives resulted in a fluorescent labeling of the cytoplasm in both intact and "freeze-damaged" cells of the three cell lines. This staining was independent of the presence of receptors. Nuclei were not stained. Incubation of intact cels with the protein-linked conjugate did not result in significant cellular fluorescence. Only cells with damaged membranes showed a positive histochemical reaction, both in nucleus and cytoplasm, irrespective of the receptor content of the cells. The fluorescence intensity was not suppressed with excess 5 alpha-dihydrotestosterone or methyltrienolone, which are known to prevent binding of low affinity ligands to androgen receptors. From these results it is concluded that androgen receptors cannot be detected by these fluorescent ligands with low affinity for the receptor. The observed fluorescence of the cells is therefore due to binding of the ligands to other binding sites. The visualization/histochemical demonstration of these binding sites does not appear to be related to the presence of androgen receptors.

Adenocarcinoma↗
PubMed1999

Regulation of expression of Na+,K+-ATPase in androgen-dependent and androgen-independent prostate cancer.

The beta 1-subunit of Na+,K+-ATPase was isolated and identified as an androgen down-regulated gene. Expression was observed at high levels in androgen-independent as compared to androgen-dependent (responsive) human prostate cancer cell lines and xenografts when grown in the presence of androgens. Down-regulation of the beta 1-subunit was initiated at concentrations between 0.01 nM and 0.03 nM of the synthetic androgen R1881 after relatively long incubation times (> 24 h). Using polyclonal antibodies, the concentration of beta 1-subunit protein, but not of the alpha 1-subunit protein, was markedly reduced in androgen-dependent human prostate cancer cells (LNCaP-FGC) cultured in the presence of androgens. In line with these observations it was found that the protein expression of total Na+,K+-ATPase in the membrane (measured by 3H-ouabain binding) was also markedly decreased. The main function of Na+,K+-ATPase is to maintain sodium and potassium homeostasis in animal cells. The resulting electrochemical gradient is facilitative for transport of several compounds over the cell membrane (for example cisplatin, a chemotherapeutic agent experimentally used in the treatment of hormone-refractory prostate cancer). Here we observed that a ouabain-induced decrease of Na+,K+-ATPase activity in LNCaP-FGC cells results in reduced sensitivity of these cells to cisplatin-treatment. Surprisingly, androgen-induced decrease of Na+,K+-ATPase expression, did not result in significant protection against the chemotherapeutic agent.

Androgens↗
PubMed2003

Receptor protein tyrosine phosphatase alpha signaling is involved in androgen depletion-induced neuroendocrine differentiation of androgen-sensitive LNCaP human prostate cancer cells.

The neuroendocrine (NE) cells represent the third cell population in the normal prostate. Results of several clinical studies strongly indicate that the NE cell population is greatly increased in prostate carcinomas during androgen ablation therapy that correlates with hormone-refractory growth and poor prognosis. However, the mechanism of NE cell enrichment in prostate carcinoma remains an enigma. We investigated the molecular mechanism by which androgen-sensitive C-33 LNCaP human prostate cancer cells become NE-like cells in an androgen-reduced environment, mimicking clinical phenomenon. In the androgen-depleted condition, androgen-sensitive C-33 LNCaP cells gradually acquired the NE-like morphology and expressed an increased level of neuron-specific enolase (NSE), a classical marker of neuronal cells. Several NE-like subclone cells were established. Biochemical characterizations of these subclone cells showed that receptor-type protein-tyrosine phosphatase alpha (RPTPalpha) is elevated and ERK is constitutively activated, several folds higher than that in parental cells. In androgen-depleted condition, PD98059, an MEK inhibitor, could efficiently block not only the activation of ERK, but also the acquisition of the NE-like morphology and the elevation of NSE in C-33 LNCaP cells. In RPTPalpha cDNA-transfected C-33 LNCaP cells, ERK was activated and NSE was elevated. In those cells in the presence of PD98059, the ERK activation and NSE elevation were abolished, following a dose-response fashion. Additionally, in constitutively active MEK mutant cDNA-transfected C-33 LNCaP cells, ERK was activated and NSE level was elevated, and cells obtained the NE-like phenotype. Our data collectively indicated that RPTPalpha signaling via ERK is involved in the NE transdifferentiation of androgen-sensitive C-33 LNCaP human prostate cancer cells in the androgen-depleted condition.

Androgens↗