Biomedical subjects

H Klocker

Publications and source records attributed to H Klocker.

At least 19 recordsLinked to original sources

PubMed2004

Characteristics of prostate cancers detected at low PSA levels.

BACKGROUND: When age-referenced PSA levels as recommended by Oesterling et al.1 were used as a biopsy criterion, only 25% of the cancers detected in a population based PSA Screening Project were organ-confined. This observation led to the decision to use low PSA levels as the sole indication for biopsy. Since 1995 age-referenced PSA levels of 1.25-3.25 ng/ml have been used in combination with a percentage free PSA cutoff of 18%. This PSA cutoff reduction led to a statistically significant migration to lower pathological stages with a decreased prostate cancer mortality in the years 1996-2001. However, concerns have been raised that screening with low PSA levels may detect clinically insignificant cancers. MATERIALS AND METHODS: We evaluated prostate cancer patients with low PSA levels in terms of heterogeneity, clinical significance, multifocality, and tumor biology including ploidy and proliferation index. RESULTS: Concerning heterogeneity the Gleason score of the needle biopsy failed to predict the Gleason score of the radical prostatectomy specimen in nearly 40% of prostate cancer patients; regarding multifocality 65% of patients with low PSA levels showed multifocal lesions and 36% exhibited tetraploid DNA distribution; more than 50% of tetraploid tumors were found in patients with tumor volumes of less than 0.5 cm(3). Ploidy correlated with the Ki-67 proliferation index, but not with tumor volume. CONCLUSIONS: These results demonstrate that small prostate cancers with low PSA levels and low tumor volumes exhibit all features of prostate cancers with higher tumor volumes and show the characteristics of malignant cancers, i.e., multifocality, tetraploidy, and high proliferative activity.

Adult↗

PubMed2004

Type IV collagenase (matrix metalloproteinase-2 and -9) in prostate cancer.

BACKGROUND: The type IV collagenases/gelatinases matrix metalloproteinase-2 (MMP-2) and -9 (MMP-9) play an important role in cancer invasion and metastasis. In the present study, we measured the expression of mRNAs and enzymatic activities of MMP-9 and -2 in prostate tissues and serum samples from men with or without prostate cancer. METHODS: A total of 44 tissue samples (three from healthy volunteers, 21 from patients with benign prostate hyperplasia, 10 from patients with localized prostate cancer and 10 from patients with metastatic disease) and 71 serum samples were collected (20 from healthy volunteers, 26 from patients with benign prostatic hyperplasia, 10 from patients with localized cancer, 15 from patients with metastatic cancer). The level of mRNA for MMP-2 and -9 was determined by semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR). The enzymatic activity of MMPs was determined by zymography. RESULTS: Expression of MMP-9 mRNA was significantly higher in malignant than in nonmalignant prostate tissues (P < 0.001), while no significant difference of MMP-2 expression was detected in different prostate tissues. Results of zymography showed that there was significant difference in the enzymatic activity of MMP-9, but not MMP-2, among normal prostate, BPH, localized and metastatic prostate cancer tissues, serum samples (P < 0.05). The active form of MMP-2, with a molecular mass of 62 kDa, was detected in normal prostate, BPH and prostate cancer tissues, but not in the serum samples. Moreover, there was a significant difference in the ratio of the active form (62 kDa) and proform (72 kDa) of MMP-2 among normal, BPH and prostate cancer tissues. This ratio was further increased in metastatic prostate cancer tissues. CONCLUSION: The activity of MMP-9 and the ratio of active form/proform of MMP-2 are associated with the progression and metastasis of prostate cancer.

Adult↗

PubMed2004

Genes differentially expressed in prostate cancer.

Because of the heterogeneity of prostate cancer knowledge about the genes involved in prostate carcinogenesis is still very limited. Previously, the use of novel high-throughput technologies offered the possibility to investigate broad gene expression profiles and thus helped to improve understanding of the molecular basis of prostate disease. Many candidate genes have been identified so far which have a more or less strong effect on prostate cancer. This vast number of gene expression changes show that it is unlikely that only one gene promotes prostate cancer. Conversely, it seems more likely that a broad network of molecular changes is involved in the complex cascade of events which lead to tumour formation and progression, respectively. A few of these novel molecular targets are currently under clinical evaluation. This paper gives an overview of several interesting candidate genes which may be useful as improved biomarkers for diagnosis or as targets for developing novel treatment methods.

Biomarkers, Tumor↗

PubMed2004

[Clinical consequences of androgen receptor malfunction].

The androgen receptor (AR), the mediator of the effects of the male sex hormones testosterone and dihydrotestosterone, plays a crucial role in development of male sex and in the function of male sexual organs. Pathological alterations of AR structure and function are a major cause of androgen insensitivity in male pseudohermaphroditism and the accompanying deformations of genital organs, or result in spinal and bulbar muscular atrophy (SBMA). In addition, AR alterations that generate a hyperreactive receptor contribute to the development of resistance to hormone ablation therapy in prostate cancer. AR mutations found in patients with male pseudohermaphroditism usually are missens mutations that result in exchange of a single amino acid and cause complete or partial loss of function. The molecular change underlaying spinal and bulbar muscular atrophy is an extension of a poly-CAG repeat in the AR gene. The affected receptor tends to form aggregates, which damage motoneurons. Androgen ablation therapy puts prostate tumor cells under selection pressure that finally results in development of a hyperreactive androgen receptor that is activated under the conditions of therapy.

Amino Acid Substitution↗

PubMed2002

[Dihydrotestosterone and the role of 5 alpha-reductase inhibitors in benign prostatic hyperplasia].

The genesis of benign prostate hyperplasia (BPH) depends on two factors: testicular androgen and the aging process. The most important androgen in the prostate is dihydrotestosterone (DHT). In the aging male the level of DHT in the prostate remains largely constant although the plasma level of testosterone decreases. DHT is formed by the reduction of testosterone by the enzyme 5-alpha-reductase, which has two isoenzymes. The 5-alpha-reductase type 2 is the predominant isoenzyme in genital tissue and thus also in the prostate. Finasteride is a 5-alpha-reductase inhibitor, which is applied in the treatment of BHP and male baldness. In the doses used finasteride acts mainly by inhibiting the 5-alpha-reductase type 2, thereby reducing the serum level of DHT by approximately 70% and by about 85-90% in the prostate. Indeed the effect of finasteride in BPH was proven in clinical studies. However, the circulating and intraprostatic DHT could be further reduced by a more effective dual 5-alpha-reductase inhibitor, which would be efficacious in the treatment of benign prostate hyperplasia and other DHT-related disorders.

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

PubMed2002

Dihydrotestosterone and the concept of 5alpha-reductase inhibition in human benign prostatic hyperplasia.

The development of human benign prostatic hyperplasia (BPH) clearly requires a combination of testicular androgens and the ageing process. Although the role of androgens as the causative factor for human benign prostatic hyperplasia is debated, they undoubtedly play, at least, a permissive role. The principal prostatic androgen is dihydrotestosterone. Although not elevated in human benign prostatic hyperplasia, dihydrotestosterone levels in the prostate remain at a normal level with ageing, despite a decrease in the plasma testosterone. Dihydrotestosterone (DHT) is generated by a reduction in testosterone. Two isoenzymes of 5alpha-reductase have been discovered. Type 1 is present in most tissues in the body where 5alpha-reductase is expressed, and is the dominant form in sebaceous glands. Type 2 5alpha-reductase is the dominant isoenzyme in genital tissues, including the prostate. Finasteride is a 5alpha-reductase inhibitor that has been used to treat BPH and male-pattern baldness. At doses used clinically, its major effect is to suppress type 2 5alpha-reductase, because it has a much lower affinity for the type 1 isoenzyme. Finasteride suppresses DHT by about 70% in serum and by as much as 85%-90% in the prostate. The remaining DHT in the prostate is likely to be the result of type 1 5alpha-reductase. The suppression of both 5alpha-reductase isoenzymes with GI198745 results in greater and more consistent containment of serum dihydrotestosterone than that observed with a selective inhibitor of type 2 5alpha-reductase. Physiological and clinical studies comparing dual 5alpha-reductase inhibitors, such as GI198745, with selective type 2, such as finasteride, will be needed to determine the clinical relevance of type 1 5alpha-reductase within the prostate. There have been two large, international multicentre, phase III trials published documenting the safety and efficacy of finasteride in treating human benign prostatic hyperplasia. Combining these two studies, randomised, controlled data are available for 12 months. Non-controlled extension of these data from a subset of patients, who elected to continue on the drug for 3, 4 and 5 years, are also available. Long-term medical therapy with finasteride can reduce clinically significant endpoints, such as acute urinary retention or surgery. According to the meta-analysis of six randomised, clinical trials with finasteride, finasteride is most effective in men with large prostates. A more effective dual inhibitor of type 1 and 2 human 5alpha-reductase may lower circulating dihydrotestosterone to a greater extent than finasteride and show advantages in treating human benign prostatic hyperplasia and other disease states that depend on dihydrotestosterone. A clinical evaluation of potent dual 5alpha-reductase inhibitors may help to define the relative roles of human type 1 and 2 5alpha-reductase in the pathophysiology of benign prostatic hyperplasia and other androgen-dependent diseases.

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

PubMed2002

Androgen receptors in prostate cancer.

The androgen receptor (AR), a transcription factor that mediates the action of androgens in target tissues, is expressed in nearly all prostate cancers. Carcinoma of the prostate is the most frequently diagnosed neoplasm in men in industrialized countries. Palliative treatment for non-organ-confined prostate cancer aims to down-regulate the concentration of circulating androgen or to block the transcription activation function of the AR. AR function during endocrine therapy was studied in tumor cells LNCaP subjected to long-term steroid depletion; newly generated sublines could be stimulated by lower concentrations of androgen than parental cells and showed up-regulation of AR expression and activity as well as resistance to apoptosis. Androgenic hormones regulate the expression of key cell cycle regulators, cyclin-dependent kinase 2 and 4, and that of the cell cycle inhibitor p27. Inhibition of AR expression could be achieved by potential chemopreventive agents flufenamic acid, resveratrol, quercetin, polyunsaturated fatty acids and interleukin-1beta, and by the application of AR antisense oligonucleotides. In the clinical situation, AR gene amplification and point mutations were reported in patients with metastatic disease. These mutations generate receptors which could be activated by other steroid hormones and non-steroidal antiandrogens. In the absence of androgen, the AR could be activated by various growth-promoting (growth factors, epidermal growth factor receptor-related oncogene HER-2/neu) and pleiotropic (protein kinase A activators, interleukin-6) compounds as well as by inducers of differentiation (phenylbutyrate). AR function is modulated by a number of coactivators and corepressors. The three coactivators, TIF-2, SRC-1 and RAC3, are up-regulated in relapsed prostate cancer. New experimental therapies for prostate cancer are aimed to down-regulate AR expression and to overcome difficulties which occur because of the acquisition of agonistic properties of commonly used antiandrogens.

Androgen Antagonists↗

PubMed2001

Melatonin elicits nuclear exclusion of the human androgen receptor and attenuates its activity.

BACKGROUND: The androgen receptor (AR) promotes growth and functionality of androgen sensitive benign and cancer tissues. The pineal hormone melatonin is an androgen protagonist in vivo and in vitro. The interference of melatonin in the AR cascade was explored. METHODS: The effects of melatonin on AR expression, level, agonist and androgen-response element (ARE) binding, reporter gene activity and intracellular localization were explored in prostate cancer LNCaP cell line. RESULTS: Melatonin increased immunoreactive AR cells in the absence and presence of dihydrotestosterone. Despite this increase and maintenance of AR agonist binding capacity, the androgen-induced reporter gene activity and suppression of AR-mRNA were attenuated. Immunocytochemical analysis and subcellular fractionation studies revealed nuclear exclusion of AR by melatonin. CONCLUSIONS: The melatonin-mediated nuclear exclusion of the AR may explain the attenuation of AR activity in the prostate cancer cells. This is the first demonstration of a hormone-induced mislocalization of the AR in prostate epithelial cells and may represent a novel route for regulating AR activity.

Androgen Receptor Antagonists↗

PubMed2001

Human rhabdosphincter cell culture: a model for videomicroscopy of cell contractions.

BACKGROUND: Physiology of the human rhabdosphincter and its innervation are still a subject to controversy. A better understanding of rhabdosphincter function and anatomy might help to solve important urological problems like urinary incontinence. It was the aim of the present study to develop a human sphincter cell culture model for investigation of contraction mechanisms in vitro. METHODS AND RESULTS Cells were isolated from human rhabdosphincter tissue obtained from prostatectomy and cystoprostatectomy specimens. Cultured cells expressed typical features of striated muscle cells. By means of videomicroscopy with a time lapse videosystem cell contractions could be documented. Under control conditions without any contractile stimulant 8% of the cells were seen to contract. Cholinergic stimulation with 10 mM of acetylcholine induced a significant increase in contraction rate to 49%. CONCLUSIONS: These results demonstrate that cholinergic stimulation triggers contraction of cultured human rhabdosphincter cells. This model might help to understand external urethral sphincter physiology and to establish new therapies for the treatment of sphincter dysfunctions. Prostate 47:189-193, 2001.

Cell Culture Techniques↗

PubMed2001

Prostate cancer mortality after introduction of prostate-specific antigen mass screening in the Federal State of Tyrol, Austria.

OBJECTIVES: To monitor the impact of screening in a natural experiment by comparing prostate cancer mortality in Tyrol, where prostate-specific antigen (PSA) testing was introduced at no charge, with the rest of Austria, where it was not introduced. METHODS: In 1993, PSA testing was made freely available to men aged 45 to 75 years in the Federal State of Tyrol, Austria. At least two thirds of all men in this age range have been tested at least once during the first 5 years of the study. Initially, only total PSA was measured, but free PSA measurement was added in 1995. The IMX assay was used. Digital rectal examination was not part of the screening examination. RESULTS: Significant migration to lower stages has been observed since the introduction of this screening program. A reduction in mortality rates in the rest of Austria from 1993 onward has occurred, with the reduction in Tyrol much greater; the mortality remained fairly constant between 1993 and 1995 and subsequently fell. The trends in prostate cancer mortality rates since 1993 differ significantly between Tyrol (P = 0.006) and the rest of Austria. On the basis of the age-specific death rates averaged from 1986 to 1990, the difference between the number of expected and observed deaths from prostate cancer in Tyrol was 22 in the group aged 40 to 79 years in 1998 and 18 the following year. CONCLUSIONS: These findings are consistent with the hypothesis that the policy of making PSA testing freely available, and the wide acceptance by men in the population, is associated with a reduction in prostate cancer mortality in an area in which urology services and radiotherapy are available freely to all patients. It is our opinion that most of this decline is likely to be due to aggressive downstaging and successful treatment and that any contribution from detecting and treating early cancers will only become apparent in the years to come.

Aged↗

PubMed2001

Expression level-dependent contribution of glucocorticoid receptor domains for functional interaction with STAT5.

The action of the glucocorticoid receptor (GR) on beta-casein gene transcription serves as a well-studied example of a case where the action of the GR is dependent on the activity of another transcription factor, STAT5. We have investigated the domain-requirement of the GR for this synergistic response in transfection experiments employing GR mutants and CV-1 or COS-7 cells. The results were influenced by the expression levels of the GR constructs. At low expression, STAT5-dependent transactivation by mutants of the GR DNA binding domain or N-terminal transactivation domain was impaired and the antiglucocorticoid RU486 exhibited a weak agonistic activity. When the N-terminal region of the GR was exchanged with the respective domain of the progesterone receptor, STAT5-dependent transactivation was reduced at low and high expression levels. Only at high expression levels did the GR exhibit the properties of a coactivator and enhanced STAT5 activity in the absence of a functional DNA binding domain and of GR binding sites in the proximal region of the beta-casein gene promoter. Furthermore, at high GR expression levels RU486 was nearly as efficient as dexamethasone in activating transcription via the STAT5 dependent beta-casein gene promoter. The results reconcile the controversial issue regarding the DNA binding-independent action of the GR together with STAT5 and provide evidence that the mode of action of the GR depends not only on the type of the particular promoter at which it acts but also on the concentration of the GR. GR DNA binding function appears to be mandatory for beta-casein gene expression in mammary epithelial cells, since the promoter function is completely dependent on the integrity of GR binding sites in the promoter.

Amino Acid Sequence↗

PubMed2001

Molecular biology of the androgen receptor: from molecular understanding to the clinic.

The androgen receptor (AR) is the key regulatory element of androgen signaling in the cell. It mediates action of androgens and is therefore essential for growth, function and differentiation of the human male urogenital tract. Genetic alterations in the AR gene may cause impaired development resulting in androgen insensitivity syndromes (AIS) or in neurodegenerative diseases like Kennedy syndrome. Besides the crucial role in the process of virilization during embryogenesis and puberty, the AR also plays an important role in the adult man as the intracellular mediator of androgen action. Androgen withdrawal and/or AR blockade is the main choice of treatment of nonorgan-confined prostate cancer. Unfortunately, this treatment is only palliative and a majority of these tumors recur and progress to an androgen-independent and therapy-resistant stage. Recent findings gave new insight into the molecular structure and function of the AR and improved our understanding about prostate cancer progression, consequently resulting in the development of novel treatments. It has become evident that the AR is a nuclear transcription factor that can be activated ligand-dependently by androgens as well as ligand-independently by other hormones and various growth factors, respectively. Moreover, it was shown that the interaction of the AR with other proteins of the intracellular signal transduction cascade may promote prostate tumor growth. This review will summarize the most important findings about the AR and the androgen signaling pathway to improve the understanding of prostate diseases and novel treatment strategies that may be useful in the clinic.

Androgen-Insensitivity Syndrome↗

PubMed2001

Photodynamic diagnosis with 5-aminolevulinic acid in the treatment of secondary urethral tumors: first in vitro and in vivo results.

OBJECTIVES: Photodynamic diagnosis (PDD) is able to detect dysplasia and transitional cell cancer of the bladder. We report our first experiences using PDD in the urethra. MATERIALS AND METHODS: Three patients with secondary transitional cell cancer of the urethra were treated by using PDD. 5-Aminolevulinic acid (ALA) was applied in a mixture with lubricant to achieve long enough contact with the urothelium. Negative effects were tested in vitro on three bladder cell lines. RESULTS: In vitro assays showed no enhanced negative effects on the viability of bladder cells using the combination of ALA/lubricant and medium in comparison to lubricant/medium alone. All patients showed markedly fluorescent areas, which were resected. The treatment was well tolerated without side effects attributable to the photosensitizer containing lubricant. CONCLUSION: Lubricant with ALA forms a viscous solution, which can successfully be used for PDD in the urethra. Thus marking tumors by fluorescence may improve transurethral resection and thus preserve the urethra.

Adult↗

PubMed2001

Androgen receptor mutations in carcinoma of the prostate: significance for endocrine therapy.

Endocrine therapy for advanced prostate cancer involves androgen ablation (orchiectomy or application of luteinizing hormone releasing hormone analogs) and/or blockade of the androgen receptor (AR) with either steroidal (cyproterone acetate) or nonsteroidal (hydroxyflutamide, bicalutamide and nilutamide) antiandrogens. These antagonists prevent androgen-induced conformational change and activation of the AR. During long term androgen ablation, the AR adapts to an environment with low androgen concentrations and becomes hypersensitive to low concentrations of androgens, either alone or in combination with various cellular regulators. Bicalutamide can switch from antagonist to agonist during long-term androgen withdrawal, as shown in prostate cancer LNCaP cells. AR point mutations were detected in metastatic lesions from human prostate cancer more frequently than in primary tumors. Although functional characterization of only some mutant AR detected in prostate cancer tissue has been performed, data available suggest that they are activated by dihydrotestosterone, its precursors and metabolites, synthetic androgens, estrogenic and progestagenic steroids and hydroxyflutamide. A direct association between AR mutations and endocrine withdrawal syndrome has been investigated in only one study thus far. There is no evidence at present that activation of any of the mutant AR genes detected in prostate cancer is enhanced in the presence of a nonsteroidal AR stimulator. Coactivators of the AR are proteins that associate with the receptor, possess histone acetylase activity and facilitate AR activation. The coregulatory proteins ARA70 and ARA160 differentially affected the activity of the mutated AR Glu(231)-->Gly, which was discovered in a mouse authochthonous prostate tumor. ARA70 enhanced receptor activation by both androgen and estradiol, whereas ARA160 augmented only androgen-induced AR activity. Novel experimental therapies that down-regulate AR expression have been developed; they include the application of ribozymes and antisense oligonucleotides.

Androgen Antagonists↗

PubMed2001

Predictive value of total and percent free prostate specific antigen in high grade prostatic intraepithelial neoplasia lesions: results of the Tyrol Prostate Specific Antigen Screening Project.

PURPOSE: We evaluate the predictive values of total and percent free prostate specific antigen (PSA) in regard to high grade intraepithelial lesions in volunteers who participated in the Tyrol PSA Screening Project. MATERIALS AND METHODS: Between June 1995 and December 1998, 1,474 patients undergoing transrectal biopsy of the prostate were evaluated. The primary detection rates of prostate cancer and high grade intraepithelial lesions were evaluated. In addition, the rate of prostate cancer detected on biopsy in patients diagnosed with high grade prostatic intraepithelial neoplasia on the previous biopsy was assessed. Mean total PSA values and mean percent free PSA levels were determined for each study group and compared using the Mann-Whitney U test. RESULTS: A total of 1,077 (73.1%) volunteers had benign prostatic hyperplasia or prostatitis, and 327 (22.2%) had prostate cancer. The primary detection rate for high grade intraepithelial lesions was 4.7% (70 patients) and on repeat biopsy was 38.6% (27). Mean total PSA for the benign prostatic hyperplasia, prostate cancer, high grade and intraepithelial cancer groups were 6.0, 8.7, 5.9 and 5.2 ng./ml., respectively. Mean percent free PSA values for the various groups were 21.9, 12.1, 15.0 and 12.0, respectively. In regard to total PSA there was a statistically significant difference between the prostate cancer and high grade prostatic intraepithelial neoplasia groups (p = 0.016), as well as the prostate cancer and intraepithelial cancer groups (p = 0.028). However, the high grade and intraepithelial cancer groups did not differ significantly. In regard to percent free PSA there were statistically significant differences between the prostate cancer and high grade prostatic intraepithelial neoplasia groups (p = 0.0001), and the high grade and intraepithelial cancer groups (p = 0.013). CONCLUSIONS: In regard to percent free PSA our data indicate a significant difference between high grade intraepithelial lesion and intraepithelial cancer. Due to a substantial overlap in percent free prostate specific antigen between the 2 groups, a clinically useful cutoff point could not be established. Therefore, we recommend repeat biopsy in all patients with high grade intraepithelial lesions regardless of the percent free PSA.

Adult↗

PubMed2001

Prostate cancer cells (LNCaP) generated after long-term interleukin 6 (IL-6) treatment express IL-6 and acquire an IL-6 partially resistant phenotype.

PURPOSE: The levels of interleukin-6 (IL-6) are frequently elevated in sera from patients with advanced prostate carcinoma. Our main objective was to investigate changes in responsiveness to IL-6 and/or androgen that occur in LNCaP cells after long-term treatment with IL-6. This in vitro model could be of clinical relevance because of its similarity with late-stage prostate carcinoma. EXPERIMENTAL DESIGN: LNCaP human prostate cancer cells were treated with IL-6 at a concentration of 5 ng/ml. After 20 passages, the new subline LNCaP-IL-6+ has been established. Passages 20-40 are referred to as low passages (LP) and passages 41-73 as high passages (HP). LNCaP cells passaged at the same time in the absence of IL-6 were used as controls (LNCaP-IL-6-). Cells were counted after treatment with either IL-6 or the synthetic androgen methyltrienolone (R1881), and cell cycle analysis was performed. Binding of IL-6 or R1881 was assessed by radioligand binding assays. Reporter gene activity was measured by chloramphenicol acetyltransferase assay. Prostate-specific antigen in LNCaP-IL-6+ supernatants was measured by an enzyme immunoassay. Expression of IL-6 mRNA and protein was assessed by reverse transcription-PCR and ELISA, respectively. RESULTS: The basal proliferation rate in HP LNCaP-IL-6+ cells was higher than that in LNCaP-IL-6- cells. IL-6 inhibited proliferation of LNCaP-IL-6- cells but not that of either LP or HP of LNCaP-IL-6+ cells. This inability to elicit a growth-inhibitory response was associated with lack of effect on cell cycle distribution in the LNCaP-IL-6+ subline. In parallel, IL-6 binding decreased gradually during long-term IL-6 treatment and, in HP, reached only 33% of the levels measured in controls. Binding of radiolabeled androgen increased 2-fold in HP LNCaP-IL-6+ cells. Reporter gene assays revealed that R1881, at nanomolar concentrations, was a more potent androgen receptor activator in LNCaP-IL-6+ than in LNCaP-IL-6- cells. However, androgen- and IL-6-induced prostate-specific antigen secretion decreased in long-term IL-6-treated cells. IL-6 cDNA fragments were detected by reverse transcription-PCR in HP LNCaP-IL-6+ cells but not in controls or LP. IL-6 protein was first detected in passage 36 of LNCaP-IL-6+ cells, and it increased in HP. CONCLUSIONS: Long-term treatment of LNCaP human prostate cancer cells with IL-6 leads to abolishment of inhibitory growth response. In contrast to control cells, the LNCaP-IL-6+ subline expresses IL-6 mRNA and protein.

Androgens↗

PubMed2000

Expression and function of androgen receptor in carcinoma of the prostate.

This article reviews recent findings on androgen receptor expression, structure, and function in carcinoma of the prostate. In this decade, it became clear that androgen-resistant prostate cancers contain androgen receptors and, therefore, regulation of androgen receptor expression and function receives considerable attention. The article summarizes findings on regulation of androgen receptor expression by androgens, growth factors, and protein kinase A activators. In addition, modulation of function of the wild-type and mutant AR is discussed. Androgen receptor functional activity is up-regulated by androgens and nonsteroidal activators, which influence transcription of androgen receptor-regulated genes in a cell type-dependent manner. This study also contains a chapter on androgen receptor-associated proteins, coactivators, and coreppressors and their possible role in pathological situations.

Cell Differentiation↗

PubMed2000

Expression of androgen receptor coregulatory proteins in prostate cancer and stromal-cell culture models.

BACKGROUND: Androgen receptor (AR) transcriptional activity is modulated by cofactor proteins. They act as costimulators, corepressors, or bridging proteins, and a disbalanced expression may contribute to the altered activity of the AR in advanced prostate cancer. We investigated the expression of a series of steroid receptor cofactors in prostate cancer cell lines, including several LNCaP sublines, and in prostate stromal cells. METHODS: Expression of cofactors was analyzed by means of RT-PCR in PC-3, Du-145, LNCaP, three sublines of LNCaP established after long-term androgen deprivation, and two strains of primary prostate stroma cells. Expression in LNCaP and LNCaP-abl cells (which represented an advanced tumor cell) was analyzed employing semiquantitative RT-PCR. RESULTS: Ten of the 12 cofactors tested were expressed in all cells analyzed (AIB1, ARA54, ARA70, CBP, cyclin D1, Her2/neu/erbB2, BAG-1/M/L, SRC-1, SMRT, and TIF2). Only ARA55 and FHL2 mRNAs were not detected in all cells. ARA55 mRNA was absent in LNCaP cells, LNCaP sublines, and DU-145 cells; FHL2 was not expressed in LNCaP cells and its derivatives. The expression pattern was identical in LNCaP cells, and the long-term androgen ablated LNCaP sublines. Moreover, comparison of expression levels in LNCaP and LNCaP-abl cells revealed a slight reduction in LNCaP-abl cells but no gross differences. CONCLUSIONS: Prostatic cells express a great number of steroid receptor cofactors. AR activity thus seems to be modulated in a very complex way in prostate cells.

Adenocarcinoma↗