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PubMed2003

Epithelial Na, K-ATPase expression is down-regulated in canine prostate cancer; a possible consequence of metabolic transformation in the process of prostate malignancy.

BACKGROUND: An important physiological function of the normal prostate gland is the synthesis and secretion of a citrate rich prostatic fluid. In prostate cancer, citrate production levels are reduced as a result of altered cellular metabolism and bioenergetics. Na, K-ATPase is essential for citrate production since the inward Na+ gradients it generates are utilized for the Na+ dependent uptake of aspartate, a major substrate for citrate synthesis. The objective of this study was to compare the expression of previously identified Na, K-ATPase isoforms in normal canine prostate, benign prostatic hyperplasia (BPH) and prostatic adenocarcinoma (PCa) using immunohistochemistry in order to determine whether reduced citrate levels in PCa are also accompanied by changes in Na, K-ATPase expression. RESULTS: Expression of Na, K-ATPase alpha1 and beta1 isoforms was observed in the lateral and basolateral plasma membrane domains of prostatic epithelial cells in normal and BPH prostates. Canine kidney was used as positive control for expression of Na, K-ATPase alpha1 and gamma isoforms. The alpha1 isoform was detected in abundance in prostatic epithelial cells but there was no evidence of alpha2, alpha3 or gamma subunit expression. In advanced PCa, Na, K-ATPase alpha1 isoform expression was significantly lower compared to normal and BPH glands. The abundant basolateral immunostaining observed in normal and BPH tissue was significantly attenuated in PCa. CONCLUSION: The loss of epithelial structure and function and the transformation of normal epithelial cells to malignant cells in the canine prostate have important implications for cellular metabolism and are accompanied by a down regulation of Na, K-ATPase.

Journal Article↗
PubMedDate not supplied

Prevalence of high-grade prostatic intraepithelial neoplasia and its relationship to serum prostate specific antigen.

OBJECTIVE: We assessed the incidence of high-grade prostatic intraepithelial neoplasia (HGPIN) in prostates removed for bladder cancer, and evaluated its correlation with preoperative serum prostate specific antigen (PSA). MATERIALS AND METHODS: We reviewed the histology of the prostate from men who underwent cystoprostatectomy for bladder cancer without known prostate pathology prior to surgery. Preoperative serum PSA levels in patients with HGPIN were analyzed. RESULTS: 61 cystoprostatectomy specimens from May 1992 to April 1999 were reviewed. High-grade prostatic intraepithelial neoplasia (PIN) was found in 46/61 (75%) of the prostate specimens, including 21/21 (100%) patients with prostatic cancer, and 25/40 (63%) patients without prostatic cancer. The mean serum PSA in men with PIN without evidence of prostatic adenocarcinoma was 1.9 ng/mL (SD=2.026). CONCLUSION: The incidence of isolated high-grade PIN was 63%. The presence of high-grade PIN does not result in a significant elevation of serum PSA.

Journal Article↗
PubMed1998

Relationship among symptom score, prostate volume, and urinary flow rates in 543 patients with and without benign prostatic hyperplasia.

BACKGROUND: Studies on the relationship among symptom score, urinary flow rate, and prostate volume in men with lower urinary tract symptoms (LUTS) continue to be of great interest. METHODS: A total of 2,418 men, aged 30-86 years, agreed to participate in an interview and to complete a questionnaire regarding voiding patterns. All subjects answering positively to one or more of the questions were submitted to a diagnostic assessment, based on the algorithm outlined by the guidelines of the International Consultation on Benign Prostatic Hyperplasia (BPH). Five hundred forty-three out of the 2,418 participants (22.45%) were evaluated. At the end of the diagnostic evaluation, 400 men with LUTS but without concomitant conditions (except BPH) known to interfere with normal voiding were selected. Descriptive statistics were used to characterize age, symptom score (International Prostate Symptom Score), prostate volume, and urinary flow rate distribution in these patients. Correlations among the aforementioned parameters were evaluated by means of a multivariate, multiple linear regression and logistic regression model. RESULTS: As reported in other studies, only weak or modest correlations were found. Moreover, the 400 cases were classified according to four age decades. The decrease in peak and mean flow rate per decade of age was similar (0.5 and 0.4 ml/sec); the increase in prostate volume and in total symptom score per decade was 3.3 cc and 0.6, respectively. In patients less than 50 years old, most of the correlations were stronger than those observed in the entire population of 400 men (age and prostate volume, c.c. 0.2864; age and peak flow rate, c.c. -0.2689; age and mean flow rate, c.c. -0.3034). However, symptom score continued to be weakly correlated with age and prostate volume (c.c. 0.0498 and 0.1966, respectively). In the last part of the study, men were assigned to different treatment strategies. Patients who were assigned to surgical treatment had higher prostate volume and IPSS and lower urinary flow rate than those assigned to nonsurgical treatment. CONCLUSIONS: We believe that the reason for the weak statistical association frequently reported in the literature is mainly the urology clinic-based population from which the patient samples were drawn. Data emerging from this analysis support the hypothesis that age is one of the principal factors influencing the relationship among symptom score, urinary flow rate, and prostate volume.

Adult↗
PubMed2001

Analysis of glycoconjugate patterns of normal and hormone-induced dysplastic Noble rat prostates, and an androgen-independent Noble rat prostate tumor, by lectin histochemistry and protein blotting.

BACKGROUND: Alteration of the expression of glycoconjugates is frequently observed in tumors. However, studies on the changes of cellular glycosylation in the early premalignant stage of prostate carcinogenesis are scarce. METHODS: The present study characterized and compared the glycoconjugates expressed in the dysplastic lateral prostate induced in Noble (Nb) rat by steroid hormones and a transplantable androgen-independent Nb rat prostatic carcinoma line (AIT) by lectin histochemistry and protein blotting. RESULTS: The results of lectin histochemistry show that the dysplastic prostatic epithelium elaborates altered patterns of glycosylation, which are distinct from the normal secretory epithelium. Some individual cells in the dysplastic epithelium were intensely labeled by the N-acetylgalactosamine (GalNAc)-specific (agglutins from Glycine max [SBA], Helix aspera [HAA], Helix pomatia [HPA], Vicia villosa [VVA], Erythrina cristigalli [ECA]) and complex-type oligosaccharide-specific (Phaseolus vulgaris agglutin [PHA-E]) lectins, indicating that these cells contained abundant GalNAc(alpha1,3)GalNAc/Gal and Gal(beta1,4)GlcNAc(alpha1,2)Man(alpha1,6) residues. These lectins also bound to some tumor cells in the AIT, suggesting that these sugar residues are common in some dysplastic and neoplastic prostatic cells. The study has also identified several lectins (agglutins from Griffonia simplicifolia [GS-I-B4], Arachis hypogaea [PNA], Ricinus communis [RCA-I], Maackia amurensis [MAA], Sambucus nigra [SNA]), which bound only to some AIT tumor cells but not to dysplastic epithelium, indicating that alpha/betaGal and sialic acid-containing glycoconjugates are expressed by neoplastic prostatic cells. The results of lectin blottings with Triticum vulgare agglutin [S-WGA] Ulex europaeus agglutin [UEA-I] and PHA-E have identified five major glycoprotein bands (of apparent molecular weights of 116, 79, 64, 61, and 57 kDa) in the microsomal fraction of testosterone plus 17beta-estradiol (T + E2)-treated lateral prostate. These lectin-reactive bands were not detected in the AIT extracts. In the AIT microsomal extract, two glycoprotein bands of molecular weights of 58 and 46 kDa were revealed by SBA and PNA. CONCLUSIONS: The present study shows that there is an increased expression of GalNAc(alpha1,3)GalNAc/Gal residues and triantennary complex-type oligosaccharides in the dysplastic epithelial cells as compared to normal secretory epithelial cells in rat lateral prostate. This altered expression of glycoconjugates revealed in the dysplastic epithelium indicates an aberrant glycosylation in the early premalignant stage of prostate carcinogenesis. The results also show that the AIT tumor cells are heterogeneous in their glycoconjugates and different from the dysplastic epithelial cells.

Animals↗
PubMed2005

Prostate carcinoma detection and increased prostate-specific antigen levels after 4 years in Dutch and Japanese males who had no evidence of disease at initial screening.

BACKGROUND: In the current study, the authors set out to investigate the possibility that increased prostate-specific antigen (PSA) levels in Dutch and Japanese men without suspicious findings at initial prostate cancer screening were indicative of the risk of newly developing clinical malignancy in the Netherlands and Japan. METHODS: Between 1992 and 2000, 2650 men ages 55-74 years who had PSA levels < 4.0 ng/mL and no suspicious findings on digital rectal examination were entered into the current study from a population-based prostate cancer screening cohort in Gunma Prefecture, Japan. In addition, between 1994 and 1997, 3163 men with the same clinical background were entered into the current study from the Rotterdam (Netherlands) Section of the European Randomized Study of Screening for Prostate Cancer (ERSPC). Prostate carcinoma incidence and the cumulative probability of freedom from PSA increases to levels > 2.0, 3.0, and 4.0 ng/mL, respectively, after 4 years of observation were compared between the Japanese and Dutch populations. The predictive value of initial PSA level, age at study entry, and geographic location also were investigated using Cox proportional hazards models. RESULTS: The overall risk of developing prostate carcinoma during the 4-year observation period was significantly higher for the ERSPC Rotterdam cohort (5.2%) compared with the Gunma cohort (1.6%). The cumulative probability of freedom from prostate carcinoma detection and freedom from an increase in PSA levels to >/= 4.0 ng/mL (PSA progression) decreased significantly with increasing initial PSA level and did not differ significantly between Japanese and Dutch patients whose initial PSA levels fell within the same range (0.0-0.9, 1.0-1.9, 2.0-2.9, or 3.0-3.9 ng/mL). Multivariate analysis also revealed that after controlling for age and initial PSA level, the probability of PSA progression was the same for Japanese and Dutch men. Initial PSA level was the only variable found to be significantly predictive of PSA progression on multivariate analysis (P < 0.0001). CONCLUSIONS: The risk of developing prostate carcinoma within a given 4-year period is greater for Dutch males ages 55-69 years compared with their Japanese counterparts, because the former have higher PSA levels. Nonetheless, there appears to be no significant difference in prostate carcinoma risk between Dutch and Japanese males whose baseline PSA levels fall within the same range.

Age Distribution↗
PubMed2002

CHC1-L, a candidate gene for prostate carcinogenesis at 13q14.2, is frequently affected by loss of heterozygosity and underexpressed in human prostate cancer.

Loss of heterozygosity (LOH) at chromosome 13q14 is one of the most recurrent anomalies observed in sporadic prostate tumors. This LOH is believed to unmask recessive mutations that inactivate a tumor-suppressor gene(s) which otherwise regulates normal cell growth and suppresses abnormal cell proliferation. Identification of potential tumor-suppressor genes within the deleted region is a way of indicating putative pathways of prostate cancer development and progression. The main target that disappears or is downregulated as a result of 13q14 loss remains to be identified. Therefore, our first concern was to find a gene located in the 13q14 region whose transcription is reduced. CHC1-L, for chromosome condensation 1-like, is mapped to the smallest common deleted region. CHC1-L expression is significantly reduced in prostate tumors compared to normal prostate tissues (p = 0.0002). In 21 of 36 (58%) primary prostate tumors studied, CHC1-L expression was reduced at least 2-fold, as measured by real-time quantitative RT-PCR; 18 of the tumors (50%) showed 13q14 LOH for at least 1 of the 5 polymorphic markers that we studied in the region, and 14 (78%) of these were among the tumors underexpressing CHC1-L. CHC1-L is alternatively spliced at its 5' end to produce 2 isoforms, of 551 and 526 aa. Analyses of CHC1-L integrity and of the quantitative expression of its variants indicate that the observed underexpression in prostate tumors is related to reduced expression of the 551 aa isoform. Although CHC1-L is not the obvious candidate given its only known homology, to RCC1, a guanine nucleotide exchange factor for the Ras-related GTPase Ran, the frequent significant decrease observed in its expression in prostate cancer associated with the difference in frequency of CHC1-L variant isoforms between normal and neoplastic prostate tissues places it in a pivotal role or possibly adjacent to a gene that has that role in prostate cancer evolution.

Alleles↗
PubMed1994

Prostate-specific antigen in screening of prostate cancer.

Prostate-specific antigen (PSA) is a well-characterized human prostate-specific glycoprotein. PSA has been shown to be the most effective immunohistologic marker for prostate cancer, as well as the most useful serologic test in staging and monitoring prostate cancer and in early detection of recurrent disease. The greatest clinical value of PSA is an aid for early detection of prostate cancer. Recent studies have indicated that PSA-based screening of the older population for organ-confined early-stage prostate cancer is an acceptable, practical, and reliable modality. The accuracy of PSA screening is within the same range as the mammogram. The cost-effectiveness of PSA is comparable to other cancer screening tests. Although the increase in the patient's survival due to PSA-based detection of early prostate cancer remains to be documented, it is generally agreed that the PSA test along with digital rectal examination (DRE) should be included in the annual physical examination for men 50 years of age or older. High-risk men are urged to commence at age 40. Asymptomatic men who have both a negative DRE and normal PSA blood test need only to continue an annual DRE and PSA check-up. Men who have a negative DRE and elevated PSA, and all those who have a suspicious DRE regardless of PSA results, should undergo further diagnostic workup, such as transrectal ultrasonography with biopsy of visible lesions. The cure rate is high with timely treatment, when prostate cancer is detected while still confined to the prostate.

Cost-Benefit Analysis↗
PubMed2002

Adrenomedullin and proadrenomedullin N-terminal 20 peptide in the normal prostate and in prostate carcinoma.

There is increasing evidence for the important role played by regulatory peptides in the physiology of the normal and neoplastic prostate. Adrenomedullin (AM) and pro-adrenomedullin N-terminal 20 peptide (PAMP) are recently discovered regulatory peptides widely expressed in the normal prostate and in prostate carcinoma. AM is produced in secretory, stroma, and endothelial cells and in neurons of the prostate ganglia. PAMP is only produced by neuroendocrine cells. The expression of AM mRNA is regulated by androgens in the rat prostate. The number of neuroendocrine cells expressing PAMP is increased in prostate carcinoma after androgen deprivation, which shows that this peptide could regulate androgen-independent prostate tumor growth. However, the roles of AM and PAMP in the normal prostate and in prostate carcinoma are yet to be elucidated.

Adrenomedullin↗
PubMed2001

Localization of angiotensin-converting enzyme in the human prostate: pathological expression in benign prostatic hyperplasia.

Benign prostatic hyperplasia (BPH) is the most common hyperplastic disease in man and it is characterized by increased cellular growth (stromal and epithelial hyperplasia) and enhanced local sympathetic tone, both of which are known to be augmented by activation of the renin-angiotensin system (RAS) in other tissues. Angiotensin-converting enzyme (ACE) is an integral component of the RAS that is responsible for the production of the active peptide angiotensin II from the inactive precursor angiotensin I. The present study was undertaken to map the anatomical localization of ACE protein and messenger ribonucleic acid (mRNA) in the normal human prostate and to establish whether their expression is pathologically altered in BPH. Human prostate samples were obtained at post-mortem and histologically defined as normal or hyperplastic. ACE protein binding/expression was determined by in vitro autoradiography and immunohistochemistry using the ACE-specific radioligand [125I]-MK351A and a mouse anti-ACE polyclonal antibody, respectively, whereas the spatiotemporal distribution of ACE mRNA was determined by in situ hybridization using 35S-labelled oligonucleotide probes. ACE protein was localized to the glandular epithelium in the human prostate. ACE binding and immunostaining were increased in BPH compared with normal (non-hyperplastic) prostate specimens [X-ray film autoradiography: normal 873+/-48 dpm/mm2 (n=8) vs. BPH 1631+/-274 dpm/mm2 (n=6), p<0.05; emulsion autoradiography: normal 3.1+/-0.5 grains/mm2 (n=6) vs. BPH 32.8+/-8.6 grains/mm2 (n=5), p<0.01]. ACE mRNA was also localized to glandular epithelial cells in the human prostate with a significant increase in ACE mRNA expression in BPH compared with the normal prostate [normal 11.04+/-2.03 grains/cell (n=220 cells total) vs. BPH 22.29+/-1.34 grains/cell (n=198 cells total), p<0.05]. The findings of the present study suggest that ACE is localized to the glandular epithelium of the human prostate and that its expression, at both protein and mRNA level, is aberrantly increased in BPH. These data support the concept that hyperactivity of the local RAS in the prostate may be involved in the pathogenesis of BPH.

Autoradiography↗
PubMed2002

Canine prostate induces new bone formation in mouse calvaria: A model of osteoinduction by prostate tissue.

BACKGROUND: Osteoblastic metastases are common in patients with advanced prostate cancer. The pathophysiology of the new bone formation at metastatic sites is not currently known, but it is hypothesized that growth factors secreted by the prostate may be involved. Unfortunately, most rodent models of prostate cancer with metastasis to bone are osteolytic and not osteoblastic. Significant osteolysis by tumor cells at metastatic sites may also lead to fractures or bone instability. Misinterpretation of new periosteal bone due to bone instability as tumor-cell osteoinduction is another disadvantage of the osteolytic models. To circumvent these problems, we have developed a model system of new bone formation in the calvaria of nude mice stimulated by normal canine prostate tissue. METHODS: Collagenase-digested normal prostate tissue was implanted adjacent to the calvaria of nude mice. Calvaria were examined at 2 weeks post-implantation for changes in the bone microenvironment by histology, calcein uptake at sites of bone mineralization, and tartrate-resistant acid phosphatase staining for osteoclasts. RESULTS: The prostate tissue remained viable and induced abundant new woven bone formation on the adjacent periosteal surface. In some cases new bone formation also was induced on the distant or concave calvarial periosteum. The new bone stained intensely with calcein, which demonstrated mineralization of the bone matrix. The new bone formation on prostate-implanted calvaria significantly increased (1.7-fold) the thickness of the calvaria compared with control calvaria. New bone formation was not induced in calvaria of mice implanted with normal canine kidney, urinary bladder, spleen, or skeletal muscle tissue, or mice with surgically-induced disruption of the periosteum. Osteoclast numbers in the medullary spaces and periosteum of calvaria were mildly increased (61%) in mice with implanted prostate tissue. CONCLUSIONS: This animal model will be useful for investigating the roles of prostate-derived growth factors on new bone formation in vivo.

Animals↗
PubMed2003

Decreased gene expression of steroid 5 alpha-reductase 2 in human prostate cancer: implications for finasteride therapy of prostate carcinoma.

BACKGROUND: Steroid 5alpha-reductase 2 (SRD5A2) catalyzes the conversion of testosterone to the more potent androgen, DHT, in the prostate. The therapeutic influence of SRD5A2 inhibitor finasteride on prostate cancer is currently unknown. The direction and extent of changes in SRD5A2 expression in disease tissues is a relevant issue in this regard. METHODS: The expression differences of SRD5A2 in tissues representative of normal, benign, and malignant growth in the human prostate were examined in parallel by comparative analysis of relevant microarray gene expression data. Semiquantitative RT-PCR was used to further verify the gene expression differences of SRD5A2. RESULTS: Consistently decreased expression of SRD5A2 was observed in 25 prostate cancer samples when compared to 25 matched normal samples and nine BPH samples. Expression differences among these samples for six other genes were presented in parallel as indicators of the direction and extent of expression changes. These additional genes include SRD5A1, Hepsin (overexpressed in prostate cancer), AMACR (overexpressed in prostate cancer), Keratin 8 (epithelial marker), smooth muscle actin (stromal marker), Nell2 (overexpressed in BPH). Semiquantitative RT-PCR verified the expression differences for SRD5A2 in six normal, six BPH, and six prostate cancer samples. CONCLUSIONS: Results from this study, combined with those from previous studies, indicate an association of prostate cancer with reduced 5alpha-reductase enzymatic activity as a result of remarkably decreased expression of the SRD5A2 gene. The implications of this study for finasteride therapy of prostate cancer are discussed.

Case-Control Studies↗
PubMed2001

High-grade prostate intraepithelial neoplasia shares cytogenetic alterations with invasive prostate cancer.

BACKGROUND: High-grade prostate intraepithelial neoplasia (PIN) is the most likely precursor of prostate adenocarcinoma. However, the relationship between this lesion and prostate cancer has not yet been established. The detection of cytogenetic changes in the lesions prior to prostate adenocarcinoma would be useful in demonstrating such a pathogenic relationship. METHODS: Twenty eight high-grade PIN cases were found among 57 specimens of radical prostatectomy performed for clinically localized prostate cancer. Fluorescence in situ hybridization (FISH) analysis using centromeric probes to enumerate chromosomes 7, 8, 10, and 12 was performed to study the numerical chromosome alterations. FISH analysis was carried out over isolated nuclei obtained from high-grade PIN areas and prostate cancer foci in the same prostatectomy specimen. RESULTS: Of the 28 suitable cases it was possible to complete the study in 26 tumor and 20 PIN areas. The remaining cases were excluded because of insufficient tissue or poor preservation. Cytogenetic alterations (aneuploidy) were found in 16 of the 26 (62%) tumors studied. The most frequent chromosome alteration was trisomy 7, detected in 12 (75%) aneuploid tumors, followed by monosomy 8 present in 5 (31%) aneuploid tumors. Trisomy 7 was also the most frequent isolated chromosome alteration since it was detected in 7 (44%) tumors. Thirteen of 20 (65%) PIN cases were aneuploid when studied by FISH. Trisomy 7, trisomy 8, and monosomy 8 were the most common cytogenetic alterations in the 20 PIN areas studied, being observed in nine (45%), six (30%), and four (20%) cases, respectively. FISH analysis showed a high correlation (75% cases) in ploidy and pattern of cytogenetic alterations between high-grade PIN areas and the paired prostate cancer focus in the same specimen. CONCLUSIONS: The above results show a cytogenetic link between high-grade PIN and prostate cancer, suggesting that the former could be an early form of prostate cancer.

Adenocarcinoma↗
PubMed2004

Interleukin-8 expression is increased in senescent prostatic epithelial cells and promotes the development of benign prostatic hyperplasia.

BACKGROUND: Benign prostatic hyperplasia (BPH) is an extremely common disease of older men characterized by increased growth of prostatic epithelial and stromal cells. Previously we showed that senescent epithelial cells accumulate in the prostate of aging men and secrete interleukin-1 alpha (IL-1 alpha). IL-8 is also present at increased levels in BPH tissues and induces expression of FGF2, a potent stromal growth factor. Therefore, we sought to determine if IL-8 is also expressed at increased levels by senescent epithelial cells and if this secreted IL-8 plays a role in the pathogenesis of BPH. METHODS: Expression of IL-8 in human BPH tissue and primary cultures of prostatic epithelial cells was analyzed using an enzyme-linked immunoabsorption assay (ELISA). Tissue senescence was assessed by a quantitative assay for senescence-associated beta galactosidase (SA-beta gal). Proliferation of primary and immortalized prostatic epithelial cells in response to IL-8 was determined by counting of cells at intervals after addition of IL-8. RESULTS: Expression of IL-8 is significantly increased in vitro when cultured prostatic epithelial cells undergo senescence. Quantitative assay of BPH tissue extracts revealed that tissue IL-8 levels are correlated with both SA-beta gal activity and prostate weight. IL-8 promotes proliferation of primary and immortalized prostatic epithelial cells in culture. CONCLUSIONS: Senescence of prostatic epithelial cells results in increased expression of IL-8, which can promote proliferation of non-senescent epithelial and stromal cells by direct and indirect mechanisms, and in this manner contributes to the increased tissue growth seen in BPH.

Cellular Senescence↗
PubMed2006

Erythropoietin stimulates growth and STAT5 phosphorylation in human prostate epithelial and prostate cancer cells.

BACKGROUND: Erythropoietin (Epo), the principal regulator of erythroid progenitor survival, growth, and differentiation, initiates its action by binding to its cognate cell surface receptor (EpoR). EpoR have been identified on a variety of non-hematopoietic cells, both normal and malignant, however, little is known about the function of EpoR on malignant cells. METHODS: RT-PCR, Western blotting, and immunohistochemistry were used to demonstrate that prostate cancer cells express EpoR at both the gene and protein level. Cell proliferation assays and STAT5 phosphorylation were used to demonstrate Epo's mitogenic action and intracellular signaling, respectively. RESULTS: We have demonstrated that transformed prostate epithelial and prostate cancer cell lines, as well as primary prostate tissue, express the EpoR. Importantly, the EpoR on prostate cells are functional, as demonstrated by the observation that each of the cell lines exhibited a dose-dependent proliferative response to Epo, and that Epo triggered STAT5b phosphorylation in the cells. CONCLUSION: Human prostatic epithelial cells and prostate cancer cells express functional EpoR, and Epo serves as a growth factor for these cells. These results have implications for our understanding of normal prostatic growth and development and of the pathobiology of human prostate cancer.

Blotting, Western↗
PubMed2006

Monomethylated selenium inhibits growth of LNCaP human prostate cancer xenograft accompanied by a decrease in the expression of androgen receptor and prostate-specific antigen (PSA).

OBJECTIVES: Epidemiological studies and prevention trials suggest selenium is a promising preventive agent for prostate cancer. Selenium-containing compounds inhibited the growth of prostate cancer cell lines including androgen sensitive LNCaP and androgen insensitive DU145 and PC3 cells in vitro. Previous study revealed a novel mechanism of selenium action in which selenium (methylseleninic acid (MSA)) markedly reduced androgen receptor (AR) signaling in prostate cancer cells, suggesting that selenium might act as an antiandrogen, which could serve as a therapeutic agent for prostate cancer. In this study, we tested whether selenium (methylselenocysteine (MSC)) affects tumor growth of human prostate cancer cells by targeting AR signaling in vivo. METHODS: Prostate tumor xenografts were established in nude mice by co-inoculating LNCaP cells with Matrigel. The mice-bearing tumors were treated with or without MSC (100 microg/mouse/day) via intraperitoneal injection for 2 weeks. The effect of MSC on tumor growth, AR, and prostate-specific antigen (PSA) expression was examined. RESULTS: Methylselenocysteine (MSC) significantly inhibited LNCaP tumor growth (P < 0.05). AR expression in tumor tissues and serum PSA levels were considerably decreased in MSC-treated mice compared to the vehicle controls. CONCLUSIONS: Pharmacological dose of MSC inhibits the growth of LNCaP human prostate cancer in vivo accompanied by a decrease in the expression of AR and PSA. These findings suggest that selenium (MSC) can serve as a therapeutic agent aimed at disruption of AR signaling for prostate cancer.

Animals↗
PubMed1982

Influence of pituitary and adrenocortical hormones on prostatic secretion protein, a major protein in rat prostate.

Prostatic secretion protein (PSP) is an androgen-sensitive, quantitatively important protein in rat ventral prostate which has been shown to inhibit the nuclear uptake and decrease the DNA-binding capacity of the androgen-receptor complex. In the present study, the influence of the pituitary, adrenals, and gonads on the concentration of PSP in the prostate was studied. Hypophysectomy decreased the concentration of PSP to about 10% of the control level, an effect similar to that obtained by castration. No effects on prostatic wet weight or PSP concentration were observed following substitution of hypophysectomized rats with human growth hormone, rat prolactin, or rat growth hormone. On the other hand, PSP concentration as well as wet weight of the prostate were normalized in hypophysectomized rats after administration of testosterone propionate. These results are in line with a direct extrahypophyseal effect of androgens on the prostate. Adrenalectomy did not affect the concentration of PSP, nor the wet weight of the prostate. Administration of estramustine decreased the wet weight of the prostate but did not affect the prostatic concentration of PSP in normal rats. Combined treatment with testosterone propionate and estramustine seemed to increase both the wet weight and the concentration of PSP more than administration of testosterone propionate alone. These results indicate a synergistic effect between estramustine and testosterone propionate.

Adrenal Cortex Hormones↗
PubMed1984

Androgen receptor binding characteristics in the cytosol of the rat dorsolateral prostate gland and the Dunning R-3327 prostatic adenocarcinoma.

The incidence of prostatic cancer is highly correlated with advanced age, and it has been suggested that changes in androgen binding may be important in age-associated alterations in growth regulatory mechanisms of prostatic epithelial cells. In this study the effects of age on androgen binding characteristics in the dorsolateral prostate glands of young and aged Copenhagen rats were determined and the binding properties in the Dunning R3327/130 subline of rat prostatic adenocarcinoma were characterized. Tritium-labeled and nonlabeled methyltrienolone analogs (R1881) were used to study the binding properties of 5 alpha-dihydrotestosterone receptor in the cytosol of tumors and prostate glands. Binding of R1881 was low but specific for the androgen receptor as shown by competition studies in which nonlabeled R1881, 5 alpha-dihydrotestosterone, and testosterone competed successfully with 3H-R1881 for binding sites, but 17 beta-estradiol and low levels of progesterone did not. In Copenhagen dorsolateral prostate, Scatchard analysis suggested a single class of binding sites. In young animals (three to five months) the average binding capacity was 10.36 fmol/mg cytosol protein with a dissociation constant (Kd) of 2.28 nmol/L. The dorsolateral prostate of aged rats (11-16 months) showed no significant difference in specific binding characteristics as compared to the younger age group. Specific binding of 3H-R1881 in R3327/130 tumor was saturable with a single class of high-affinity binding sites having an average binding capacity of 64.77 fmol/mg cytosol protein and a Kd of 2.76 nmol/L. These data show that the tumor had approximately 6.5 times the number of binding sites as did the normal Copenhagen rat dorsolateral prostate gland. However, no age-related changes were detected through 11-16 months of age in the androgen binding characteristics of normal rat dorsolateral prostate gland that could be correlated with the higher concentration of androgen binding sites in the R3327/130 tumor subline.

Adenocarcinoma↗
PubMed1986

In vitro stimulation by prostate extracts of rat ventral prostate stromal and epithelial cell division.

We examined the effect of prostate cell extracts on the replication of highly enriched rat ventral prostate stromal and epithelial cells cultured in RPMI-1640. Extracts from normal rat prostates completely inhibited cell division in both fractions, while a 10% (v/v) extract of Dunning R-3327G adenocarcinoma inhibited replication of stromal cells but permitted that of epithelial cells. The cytotoxic effect of prostate extracts was dialyzable, heat stable, unaffected by proteases, soluble in acid/alcohol, and insoluble in chloroform. These properties are consistent with those of polyamines incubated in the presence of fetal calf serum. Dialyzed extracts from Dunning adenocarcinomas, and from human benign hypertrophic and carcinomatous prostates stimulated rat prostate stromal and epithelial cell division, in keeping with other reports of "growth factors" in prostate tissue. This mitogenic activity was stable to temperature (70 degrees C, 4 hours), and marginally if at all affected by exposure to trypsin or to pronase coupled to Sephadex. Short-term culture of separated prostate cells should provide a useful assay system for detecting putative autocrine or paracrine stromal and/or epithelial cell growth factors and identifying suspected homo- or heterotypic cellular interactions in normal and diseased prostates.

Adenocarcinoma↗