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PubMed2005

Identification of androgen-responsive genes that are alternatively regulated in androgen-dependent and androgen-independent rat prostate tumors.

The vast majority of androgen-dependent prostate tumors progress toward incurable, androgen-independent tumors. The identification of androgen-responsive genes, which are still actively transcribed in the tumors of patients who have undergone androgen ablation, may shed light on the molecular mechanisms underlying this phenomenon. To address this question, we chose the Dunning R3327 rat model system, in which the progression from androgen-dependent to -independent tumors is represented by several transplantable prostate-derived tumors. Gene expression profiles were analyzed in normal rat prostates and in the prostates of rats 14 days after castration by use of microarrays containing approximately 5,000 oligonucleotides, together representing more than 4,800 known rat genes. These expression profiles were compared with similarly obtained expression profiles of androgen-dependent and androgen-independent rat prostate tumors. By doing so, a series of known and novel prostate cancer-associated androgen-responsive genes was identified. Within this series, we were able to identify several clusters of genes that are differentially regulated in the various prostate tumors. These genes may serve as (i) novel prognostic identifiers and (ii) novel therapeutic targets.

Androgens↗
PubMed1983

Regulation of the androgen receptor by androgen in normal and androgen-resistant genital skin fibroblasts.

Normal genital skin fibroblast (GSF) monolayers incubated with serum-free medium containing 3 nM [3H]-5 alpha-dihydrotestosterone (DHT) at 37 degrees C for 20 h have about 35% more specific DHT-binding than replicates incubated in serum-free medium with [3H]-DHT for only 1 h to saturate basal specific androgen-receptor activity. If, after 19 h, spent medium is replaced by fresh medium with 3 nM [3H]-DHT for 1 h, specific DHT binding is 85% more than basal. The acquisition of increased binding is temperature dependent (37 greater than 27 degrees C) and cycloheximide (2 microM) suppressible. The increased binding activity is considered to represent an augmentation of androgen receptor concentration because it has the same equilibrium dissociation constant (KD approximately 0.5 nM), rate constant of dissociation (k-1 approximately 6 x 10(-3) min-1) and ligand specificity as basal androgen-receptor activity, and because basal DHT-binding activity is stable in cells preincubated in androgen-free or serum-free medium alone for up to 72 h before assay. Prolonged incubation with methyltrienolone (R1881), a nonmetabolizable synthetic androgen, causes a greater, more persistent increment of androgen receptor activity than does equimolar DHT. The fibroblasts from two subjects with receptor-positive, partial androgen resistance lose their basal receptor activity during prolonged incubation with DHT, but augment it normally with R1881. This suggests that defective DHT metabolism is somehow involved in the pathogenesis of their androgen resistance.

Cycloheximide↗
PubMed2004

Ectopic expression of the amino-terminal peptide of androgen receptor leads to androgen receptor dysfunction and inhibition of androgen receptor-mediated prostate cancer growth.

Androgen receptor (AR) is a ligand-activated transcription factor that requires androgen binding to initiate a series of molecular events leading to specific gene activation. AR has been suggested to form an antiparallel homodimer based on the characteristics of high affinity interaction between the amino (N) and carboxyl (C) termini of it. Recently, it is suggested that AR N-to-C interaction is critical for the ability of this receptor to up-regulate the transcription of androgen-responsive genes, and may be a new target for treatment of prostate cancer (PCa). In this study, we investigated the effect of N-terminal (1-34) peptide of AR (ARN34) on androgen-dependent function in PCa cell. Ectopic expression of ARN34 suppressed both androgen-dependent AR N-to-C interaction and prostate specific antigen transcription. Ectopic expression of ARN34 also caused delaying translocation to the nucleus and the decreasing stability of the AR. Stable expression of ARN34 suppressed androgen-dependent cell growth of LNCaP cells. Moreover, transactivation and cell growth of the AR variant in LNCaP cells by the AR antagonist, hydroxyflutamide, were also inhibited by ARN34. Although treatment of LNCaP cells with androgen drove transition of cells from G1 to S-phase, the cells expressing ARN34 were inhibited to enter into S phase in the presence of androgen. This cell cycle arrest was attended by decrease in cyclin E levels and cyclin-dependent-kinase 2 activity, and increase in p27 levels. Our results demonstrated that disruption of AR N-to-C interaction caused by ARN34 leads to AR dysfunction and inhibition of AR-mediated prostate cancer cell growth. This approach is thus considered to provide a useful therapeutic opinion for blocking AR-mediated PCa growth.

Active Transport, Cell Nucleus↗
PubMed2002

Androgen replacement therapy with dehydroepiandrosterone for androgen insufficiency and female sexual dysfunction: androgen and questionnaire results.

During our evaluations of women with sexual dysfunction, we have seen many with low interest, arousal, and orgasmic capabilities with associated personal distress and diminished genital sensation and blood flow following sexual stimulation. Laboratory evaluation of these women has revealed normal estrogen but androgen values that were either below or in the lower quartile of the physiologic range. Androgen insufficiency and sexual dysfunction have been the working diagnoses in these women. Although many treatment options currently are available for this syndrome, there are limited data concerning safety and efficacy. The aim of this retrospective, Institutional Review Board (IRB)--approved, single-institution study was to report on the androgen and questionnaire results from a series of patients who underwent androgen replacement therapy with dehydroepiandrosterone for treatment of androgen insufficiency and sexual dysfunction. This study revealed that there was a significant decrease in sexual distress, a significant increase in sexual function in the domains of desire, arousal, lubrication, satisfaction, and orgasm, and a normalization to values within the physiologic range in the following androgens measured: total testosterone, free or bioavAilable testosterone, DHEA, DHEA-S, and androstenedione. Side effects included increased facial hair (11%), weight gain (7%), acne (5%), temporary breast tenderness (1%), loss of head hair (1%) and skin rash (1%). Preliminary results suggest that androgen replacement therapy with dehydroepiandrosterone is a safe and effective treatment for androgen insufficiency and female sexual dysfunction. However, further research is needed, including prospective, multi-institution, placebo-controlled double-blind studies.

Adjuvants, Immunologic↗
PubMed1989

Androgen resistance associated with a qualitative abnormality of the androgen receptor and responsive to high dose androgen therapy.

A 46,XY infant with perineoscrotal hypospadias and microphallus was identified in a family in which seven individuals have severe hypospadias that is inherited in a pattern compatible with an X-linked defect. The infant had small testes that were palpable in the labioscrotal folds, the proximal urethra was male in character, and there was no vagina. Serum testosterone rose from 0.5 to 5.1 nmol/L in response to hCG, and there was a negligible clinical response to a short term course of testosterone enanthate. A clinical diagnosis of male pseudohermaphroditism due to androgen resistance was made. Studies in cultured genital skin fibroblasts disclosed normal 5 alpha-reductase activity, a normal amount of high affinity dihydrotestosterone binding, and normal up-regulation of androgen receptors when monolayers were incubated with dihydrotestosterone or mibolerone. Fibroblast cytosol preparations contained a normal 7-8S sedimenting peak of androgen binding. However, androgen binding in monolayers decreased 60% when the assay temperature was raised from 30 to 41 C, and the dissociation rate of ligand from the receptor was enhanced 5-fold compared to the control value, establishing the diagnosis of androgen resistance due to a qualitative abnormality of the androgen receptor. Because of parental decision to raise the patient as a male, he was given two courses of high dose testosterone cypionate when he was 2.5 and 3.5 yr old (100 mg every 2 weeks for six doses). This treatment produced significant phallic growth, making it possible to undertake surgical correction of the hypospadias. We postulate that the impairment of androgen receptor function was overcome in part by the large dose of androgen.

Chorionic Gonadotropin↗
PubMed2006

Differential regulation of IGFBP-3 by the androgen receptor in the lineage-related androgen-dependent LNCaP and androgen-independent C4-2 prostate cancer models.

BACKGROUND: Despite evidence implicating insulin-like growth factor binding protein-3 (IGFBP-3) as a growth inhibitor of prostate cancer (CaP), little is known about changes in its regulation and function during progression to androgen independence. METHODS: The expression levels of IGFBP-3 were determined by cDNA microarray analysis and tissue microarrays (TMAs) after androgen ablations. LNCaP (LN-BP3) and C4-2 (C4-2-BP3) sublines were used to compare the apoptotic effects of IGFBP-3 in LNCaP (androgen-dependent) and C4-2 (androgen-independent) cells. RESULTS: After androgen deprivation, IGFBP-3 mRNA levels increased more in C4-2 compared to LNCaP cells. Androgens suppressed IGFBP-3 levels in a dose-dependent manner in LNCaP and C4-2 cell. IGFBP-3 expression was increased after NHT in human CaP tissues. Apoptotic rates increased in LN-BP3, but not C4-2-BP3 cells, following doxycycline-mediated IGFBP-3 induction. CONCLUSIONS: C4-2 cell survival in an androgen-depleted environment may be facilitated through differential resistance to the apoptotic effects elicited by IGFBP-3.

Androgens↗
PubMed1982

Relative binding affinities of testosterone, 19-nortestosterone and their 5 alpha-reduced derivatives to the androgen receptor and to other androgen-binding proteins: a suggested role of 5 alpha-reductive steroid metabolism in the dissociation of "myotropic" and "androgenic" activities of 19-nortestosterone.

The relative binding affinities of testosterone (T), 19-nortestosterone (N) and their 5 alpha-reduced derivatives: 5 alpha-dihydrotestosterone (DHT) and 5 alpha-dihydro-19-nortestosterone (DHN) to the androgen receptor of the rat seminal vesicle was studied using competition experiments. In cell-free extracts incubated at +10 degrees C for 18 h the relative binding affinities of these steroids (DHT greater than T = DHN = N) proved to be specific for the androgen receptor, in the sense that only prostatic extracts gave a similar result while three other androgen binding proteins (human sex steroid binding globulin, rat epididymal androgen binding protein and an antibody raised against T) exhibited quite different binding specificities. In minced seminal vesicles incubated at 37 degrees C for 1 h the binding affinities showed marked differences (DHT greater than N greater than T greater than or equal to DHN) and similar patterns were observed with both the cytoplasmic and the nu clear receptors. Our findings suggest that (I) the simultaneous presence of a 4-ene double bond and 19-methyl group in T does not favor the tight binding of T to the androgen receptor; therefore, either saturation of this double bond or elimination of the 19-methyl group leads to increased binding and (II) while 5 alpha-reduction of T increases the affinity of this steroid to the receptor, that of N does not influence or rather tends to decrease the binding affinity. The opposite changes observed in the binding affinities of T and N after their 5 alpha-reduction may account for the lower androgenicity of N. On the other hand, the relative myotropic activity in vivo of these steroids is apparently determined by the ratio of their affinities (N/T approximately 3 at 37 degrees C) to the androgen receptor.

Androgen-Binding Protein↗
PubMed2002

Bcl-2 and androgen receptor gene expression in androgen-independent subclone derived from mouse androgen-dependent cells.

We investigated bcl-2 and androgen receptor (AR) expression in an androgen-independent subline derived from mouse androgen-dependent mammary carcinoma cells. The androgen-independent SCAI cells were subcloned by cultivating androgen-dependent SC2G cells in serum-free, androgen-free conditions. The growth of the SCAI cells was not affected by testosterone. Western blot analysis showed greater expression of Bcl-2 protein in SCAI cells than in SC2G cells. A four-day culture with 4 microM antisense oligonucleotide complementary to mouse bcl-2 significantly decreased the viability of SCAI cells, when compared with sense control. The amount of the AR-mRNA expression in SCAI cells was slightly weaker. Direct sequence analysis showed no mutations in the AR of either androgen-dependent or -independent cells. These data indicate that the increased expression of Bcl-2 protein plays an important role in acquiring tolerance for the testosterone ablation, although it is not related to AR gene alteration.

Androgens↗
PubMed1990

Androgen receptor defects in patients with minimal and partial androgen resistance classified according to a model of androgen-receptor complex energy states.

We have characterized intracellularly the androgen-receptor (A-R) complexes formed by genital skin fibroblasts from 2 unrelated males with qualitative defects of the androgen receptor: one has a small nonhypospadic penis as part of a syndrome of mild androgen resistance; the other was born with ambiguous external genitalia. The dissociation rate constants of testosterone, methyltrienolone (MT), dihydrotestosterone (DHT) and mibolerone (MB) from normal androgen receptors were determined at various temperatures: when plotted by the method of Arrhenius, they yielded a linear hierarchy of dissociation states with energies of state IV greater than III greater than II greater than I, respectively. Relative to this hierarchy, patient A-R complexes were displaced to higher, androgen-inappropriate energies in a mutant-distinctive pattern. MB- or MT-R complexes of both patients were thermolabile; however, both up-regulated normally in response to prolonged incubation with either hormone. Apparent equilibrium affinity constants (Kd) of the DHT- and MB-R complexes formed by both patients were normal; however, the binding capacity (Bmax) for MB in 1 case was subnormal. The distinctive biochemical phenotypes of A-R complexes in these 2 patients with androgen resistance will facilitate the definition of structure-function relations in the androgen receptor, a classical DNA-binding, transcription-regulating protein.

Adolescent↗
PubMed1990

Definition of the human androgen receptor gene structure permits the identification of mutations that cause androgen resistance: premature termination of the receptor protein at amino acid residue 588 causes complete androgen resistance.

We have isolated and characterized the gene encoding the human androgen receptor. The coding sequence is divided into eight coding exons and spans a minimum of 54 kilobases. The positions of the exon boundaries are highly conserved when compared to the location of the exon boundaries of the chicken progesterone and human estrogen receptor genes. Definition of the intron/exon boundaries has permitted the synthesis of specific oligonucleotides for use in the amplification of segments of the androgen receptor gene from samples of total genomic DNA. This technique allows the analysis of all segments of the androgen receptor gene except a small region of exon 1 that encodes the glycine homopolymeric segment. Using these methods we have analyzed samples of DNA prepared from a patient with complete androgen resistance and have detected a single nucleotide substitution at nucleotide 1924 in exon 3 of the androgen receptor gene that results in the conversion of a lysine codon into a premature termination codon at amino acid position 588. The introduction of a termination codon into the sequence of the normal androgen receptor cDNA at this position leads to a decrease in the amount of mRNA encoding the human androgen receptor and the synthesis of a truncated receptor protein that is unable to bind ligand and is unable to activate the long terminal repeat of the mouse mammary tumor virus in cotransfection assays.

Amino Acid Sequence↗
PubMed1999

The anti-androgen hydroxyflutamide and androgens inhibit interleukin-6 production by an androgen-responsive human osteoblastic cell line.

While androgens clearly have significant skeletal effects, the paracrine mediators of androgen action on bone are at present unclear. Interleukin-6 (IL-6) is a candidate cytokine that is produced by osteoblastic lineage cells and promotes osteoclastogenesis and bone resorption. Here, we assessed constitutive as well as IL-1beta- and tumor necrosis factor-alpha (TNF-alpha)-stimulated IL-6 mRNA expression by Northern analysis and protein secretion by immunoassay in a human androgen-responsive osteoblastic cell line (hFOB/AR-6) which contains approximately 4000 androgen receptors (ARs)/nucleus. Treatment with 5alpha-dihydrotestosterone (DHT) dose-dependently inhibited constitutive and TNF-alpha/IL-1beta-stimulated IL-6 mRNA steady-state levels in hFOB/AR-6 cells by 70-80% at 10-7 M. In addition, testosterone also suppressed TNF-alpha/IL-1beta-stimulated IL-6 mRNA levels by 57%, while the adrenal androgen dehydroepiandrosterone had no effect. Of note, the specific AR antagonist, hydroxyflutamide, also inhibited IL-6 mRNA levels by 70%. Consistent with the Northern analyses, treatment with 5alpha-DHT, testosterone, and hydroxyflutamide also inhibited IL-6 protein production by 79%, 62%, and 71%, respectively (p < 0.001), while these agents had no effect on IL-6 soluble receptor levels. Finally, we demonstrated that hydroxyflutamide treatment of hFOB/AR-6 cells markedly inhibited the activation and binding of NF-kappaB (a known stimulator of IL-6 gene transcription) to its response element, thus providing a potential mechanism for its effect on IL-6 production by osteoblasts. These data are consistent with the hypothesis that suppression of osteoblast IL-6 production by androgens may mediate, at least in part, the antiresorptive effects of androgens on bone. Moreover, our findings also indicate that hydroxyflutamide, which is a known AR antagonist in most tissues, may function as a selective AR modulator for effects on IL-6 production by osteoblasts.

Analysis of Variance↗
PubMed1986

Androgen levels and androgenization in sex-reversed (XXSxr pseudomale) mouse: absence of initial segment of epididymis is independent of androgens.

The XXSxr pseudomale ("sex-reversed") mouse has an apparently normal male phenotype. This is in accordance with Jost's Principle that, in an animal with androgen-producing testes, phenotype will be fully masculinized, irrespective of chromosomal sex. However, the epididymis of this mutant lacks the Initial Segment. Several alternative explanations were proposed. In the present study we examined the primary of these, viz, androgen insufficiency. We studied androgen levels in serum and tissues of the mutant, and we investigated whether injection of exogenous androgens could induce normal development. The XXSxr pseudomale is not deficient in androgens, nor do exogenous additional androgens induce development of the Initial Segment. It would appear that the abnormal genotype acts on the organ phenotype without intervention of androgens.

Androgens↗
PubMed2005

Androgen receptor down regulation by small interference RNA induces cell growth inhibition in androgen sensitive as well as in androgen independent prostate cancer cells.

We investigated the effects of androgen receptor (AR) down regulation with a small interference RNA molecule (siRNA_AR(start)) on androgen sensitive LNCaP and androgen independent LNCaPabl prostate cancer cells, the latter representing an in vitro model for the development of therapy resistance in prostate cancer. Although LNCaPabl cells express increased levels of AR in comparison with androgen sensitive LNCaP cells, the protein was significantly down regulated in response to siRNA_AR(start) treatment. This AR down regulation resulted in a marked cell growth inhibition in both cell lines. By contrast, DU-145 prostate cancer cells, which lack AR expression, were not inhibited by the siRNA_AR(start). In consequence to AR down regulation, both cell lines, LNCaP and LNCaPabl, shared a highly similar gene expression profile in terms of major changes in cell cycle regulatory genes. The cell cycle inhibitor p21(Waf1/Cip1) as well as cyclin D1 were significantly up regulated by siRNA_AR(start) treatment, considering a switch in cyclin expression towards cell cycle retardation. Control molecules had moderate effects on cell proliferation and gene expression, respectively. In summary, we found that AR inhibition with siRNA induces cell growth retardation in androgen sensitive as well as in androgen independent prostate cancer cells and thus may represent an interesting approach to combat hormone-refractory prostate cancer.

Androgen Receptor Antagonists↗
PubMed1999

Discordant measures of androgen-binding kinetics in two mutant androgen receptors causing mild or partial androgen insensitivity, respectively.

We have characterized two different mutations of the human androgen receptor (hAR) found in two unrelated subjects with androgen insensitivity syndrome (AIS): in one, the external genitalia were ambiguous (partial, PAIS); in the other, they were male, but small (mild, MAIS). Single base substitutions have been found in both individuals: E772A in the PAIS subject, and R871G in the MAIS patient. In COS-1 cells transfected with the E772A and R871G hARs, the apparent equilibrium dissociation constants (Kd) for mibolerone (MB) and methyltrienolone are normal. Nonetheless, the mutant hAR from the PAIS subject (E772A) has elevated nonequilibrium dissociation rate constants (k(diss)) for both androgens. In contrast, the MAIS subject's hAR (R871G) has k(diss) values that are apparently normal for MB and methyltrienolone; in addition, the R871G hAR's ability to bind MB resists thermal stress better than the hAR from the PAIS subject. The E772A and R871G hARs, therefore, confer the same pattern of discordant androgen-binding parameters in transfected COS-1 cells as observed previously in the subjects' genital skin fibroblasts. This proves their pathogenicity and correlates with the relative severity of the clinical phenotype. In COS-1 cells transfected with an androgen-responsive reporter gene, trans-activation was 50% of normal in cells containing either mutant hAR. However, mutant hAR-MB binding is unstable during prolonged incubation with MB, whereas normal hAR-MB binding increases. Thus, normal equilibrium dissociation constants alone, as determined by Scatchard analysis, may not be indicative of normal hAR function. An increased k(diss) despite a normal Kd for a given androgen suggests that it not only has increased egress from a mutant ligand-binding pocket, but also increased access to it. This hypothesis has certain implications in terms of the three-dimensional model of the ligand-binding domain of the nuclear receptor superfamily.

Amino Acid Sequence↗
PubMed1989

Mechanism of androgen action: recent observations on the domain structure of androgen receptors and the induction of EGF-receptors by androgens in prostate tumor cells.

In this paper two different aspects of androgen action are reviewed. Polyacrylamide gel electrophoresis of androgen receptors, photoaffinity labeled with R1881 showed that receptors isolated from both human prostate cells and calf uterine cytosol cells are proteins with a molecular mass of approx 110 kD. Purification to homogeneity of this form of the receptor from calf uterus also yielded a 110 kD protein. A molecular model for the DNA-binding form of the receptor is presented in which one polypeptide comprises three active domains: one for ligand binding, one for interaction with nuclear acceptor sites, and a third domain which modulates nuclear interaction. Mild digestion with chymotrypsin or a protease from rat prostates removes the modulating domain and leaves the ligand binding and nuclear interaction domain intact. Trypsin treatment yields a fragment of lower molecular mass containing the ligand binding domain with some affinity for RNA, but not DNA. In vitro studies with a human prostate tumor cell line (LNCaP), suggest that androgens not only directly effect cell growth, but also act indirectly. Both epidermal growth factor (EGF) and androgens stimulate cell growth. In addition androgens stimulate synthesis of receptors for EGF. Thus androgens effect tumor cell growth by autocrine or paracrine mechanisms by making the cells more sensitive for growth factor mediated stimuli.

Androgens↗
PubMed1998

Response to androgen treatment in a patient with partial androgen insensitivity and a mutation in the deoxyribonucleic acid-binding domain of the androgen receptor.

Supplemental androgen therapy has enhanced virilization in only a few patients with partial androgen insensitivity (PAIS). We herein report on virilization in a patient with PAIS and a point mutation in the DNA-binding domain of the androgen receptor. At the age of 19 yr, the patient sought medical attention because of undervirilization. Endocrine findings were typical for androgen insensitivity, but 5alpha-reductase activity and androgen binding characteristics in fibroblasts cultured from genital skin were normal. In an attempt to improve virilization, high dose testosterone enanthate treatment (250 mg by i.m. injection once a week) was begun. After 3.5 yr of this treatment, marked promotion of virilization was achieved, i.e. lowering of voice, male pattern secondary hair distribution, marked growth of beard and coarse body hair, increase in phallic size, increase in bone mineral density, and decrease in mammary gland size. In addition, serum lipid levels were not affected. To our knowledge this is the first documentation of successful treatment in a patient with PAIS and a point mutation in the DNA-binding domain of the androgen receptor.

Adult↗
PubMed1999

Activation of Rb and decline in androgen receptor protein precede retinoic acid-induced apoptosis in androgen-dependent LNCaP cells and their androgen-independent derivative.

Androgen ablation-induced prostate cancer regression is transient and ends with the regrowth of androgen-independent (AI) tumors. To mimic this evolution in culture, we chronically deprived an androgen-dependent (AD) prostate cancer cell line (LNCaP) of androgen, generating an AI derivative which retained limited hormone proliferative responsiveness and a barely detectable prostate-specific antigen (PSA) mRNA level. While the cytokeratin 8 (CK8) level was low, the androgen receptor (AR) protein in AI cells was on average tenfold greater than in AD cells. When challenged for susceptibility to undergo apoptosis, the AI cells were more resistant than AD cells to all-trans retinoic acid (tRA) and two chemotherapeutic agents, Taxol and Adriamycin, requiring higher doses and longer periods of treatment to achieve similar effects. Compared to AD cells, the partially apoptosis-resistant AI cells expressed four times more Bcl-2 protein and undetectable levels of p21/WAF1. Induction of apoptosis by tRA in both cell types did not affect their expression but was preceded by the activation of Rb and a pronounced reduction of AR protein level. The kinetics of the Rb activation and AR downmodulation in both cell types matched their tRA sensitivity, suggesting that these events may be required for tRA-induced apoptosis. The results show that the apoptotic pathway in AI cells, although more difficult to induce, is not irrevocably lost and that targeted reduction of the AR protein level with retinoids in combination with androgen ablation therapy may prolong remissions in advanced prostate cancer patients.

Antigens, Surface↗
PubMed2000

Androgen and taxol cause cell type-specific alterations of centrosome and DNA organization in androgen-responsive LNCaP and androgen-independent DU145 prostate cancer cells.

We investigated the effects of androgen and taxol on the androgen-responsive LNCaP and androgen-independent DU145 prostate cancer cell lines. Cells were treated for 48 and 72 h with 0.05-1 nM of the synthetic androgen R1881 and with 100 nM taxol. Treatment of LNCaP cells with 0.05 nM R1881 led to increased cell proliferation, whereas treatment with 1 nM R1881 resulted in inhibited cell division, DNA cycle arrest, and altered centrosome organization. After treatment with 1 nM R1881, chromatin became clustered, nuclear envelopes convoluted, and mitochondria accumulated around the nucleus. Immunofluorescence microscopy with antibodies to centrosomes showed altered centrosome structure. Although centrosomes were closely associated with the nucleus in untreated cells, they dispersed into the cytoplasm after treatment with 1 nM R1881. Microtubules were only faintly detected in 1 nM R1881-treated LNCaP cells. The effects of taxol included microtubule bundling and altered mitochondria morphology, but not DNA organization. As expected, the androgen-independent prostate cancer cell line DU145 was not affected by R1881. Treatment with taxol resulted in bundling of microtubules in both cell lines. Additional taxol effects were seen in DU145 cells with micronucleation of DNA, an indication of apoptosis. Simultaneous treatment with R1881 and taxol had no additional effects on LNCaP or DU145 cells. These results suggest that LNCaP and DU145 prostate cancer cells show differences not only in androgen responsiveness but in sensitivity to taxol as well.

Androgens↗