oxytocin and Prostatic-Neoplasms

In this review, the role of oxytocin and oxytocin-like agents (acting via the oxytocin receptor and belonging to the oxytocin-family) in the male reproductive tract is considered. Previous research (dating back over 60 years) is revised and connected with recently found aspects of the role oxytocin plays in male reproductive health. The local expression of oxytocin and its receptor in the male reproductive tract of different species is summarized. Colocalization and possible crosstalk to other agents and receptors and their resulting effects are discussed. The role of the newly reported oxytocin focused signaling pathways in the male reproductive tract, other than mediating contractility, is critically examined. The structure and effect of the most promising oxytocin-agonists and -antagonists are reviewed for their potential in treating male disorders with origins in the male reproductive tract such as prostate diseases and ejaculatory disorders.

Topics: Animals; Arginine Vasopressin; Genitalia, Male; Hormone Antagonists; Humans; Male; Oxytocin; Prostatic Neoplasms; Receptors, Oxytocin; Signal Transduction

Oxytocin is a peptide hormone produced by the neurohypophysis. The discovery that the peptide is produced locally within the male and female reproductive tracts has raised the possibility that oxytocin may have paracrine and autocrine actions outside of the nervous system. Oxytocin and its receptor have been identified in the human prostate. The prostate is an androgen-dependent organ whose function is to secrete components of the seminal fluid. Oxytocin has been shown to modulate contractility of prostate tissue and also to regulate local concentrations of the biologically active androgens. Oxytocin has also been shown to regulate cell growth. Prostate disease is common and results from abnormal growth of the gland. Oxytocin concentrations are altered in both benign and malignant prostate diseases and in vitro studies suggest that the peptide may be involved in the pathophysiology of these diseases.

Topics: Humans; Male; Oxytocin; Paracrine Communication; Prostate; Prostatic Neoplasms

It is now well established that the peptide oxytocin can act as a paracrine factor as well as a classic hormone. Oxytocin is produced locally in both the testis and ovary, where it may modulate both steroidogenesis and contractility of the male and female reproductive tracts. The peptide is also present in the prostate and seminal fluid and there is growing evidence that oxytocin may be produced in the prostate. Within the prostate, oxytocin has been shown to increase growth of the epithelial tissue and increase both muscular tone and contractile activity. Furthermore, prostatic concentrations of the peptide are regulated by androgens. It is hypothesized that oxytocin may act as a paracrine factor to regulate cell growth and that this may be secondary to its effects on the enzyme 5 alpha-reductase which converts testosterone to dihydrotestosterone. In addition, oxytocin may be involved in the pathophysiology of benign prostatic hyperplasia.

Topics: Humans; Male; Oxytocin; Paracrine Communication; Prostate; Prostatic Hyperplasia; Prostatic Neoplasms

Tumor cell motility is the essential step in cancer metastasis. Previously, we showed that oxytocin and epidermal growth factor (EGF) effects on cell migration in prostate cancer cells require Giα2 protein. In the current study, we investigated the interactions among G-protein coupled receptor (GPCR), Giα2, PI3-kinase, and Rac1 activation in the induction of migratory and invasive behavior by diverse stimuli. Knockdown and knockout of endogenous Giα2 in PC3 cells resulted in attenuation of transforming growth factor β1 (TGFβ1), oxytocin, SDF-1α, and EGF effects on cell migration and invasion. In addition, knockdown of Giα2 in E006AA cells attenuated cell migration and overexpression of Giα2 in LNCaP cells caused significant increase in basal and EGF-stimulated cell migration. Pretreatment of PC3 cells with Pertussis toxin resulted in attenuation of TGFβ1- and oxytocin-induced migratory behavior and PI3-kinase activation without affecting EGF-induced PI3-kinase activation and cell migration. Basal- and EGF-induced activation of Rac1 in PC3 and DU145 cells were not affected in cells after Giα2 knockdown. On the other hand, Giα2 knockdown abolished the migratory capability of PC3 cells overexpressing constitutively active Rac1. The knockdown or knockout of Giα2 resulted in impaired formation of lamellipodia at the leading edge of the migrating cells. We conclude that Giα2 protein acts at two different levels which are both dependent and independent of GPCR signaling to induce cell migration and invasion in prostate cancer cells and its action is downstream of PI3-kinase-AKT-Rac1 axis.

Topics: Cell Line, Tumor; Cell Movement; Cell Proliferation; Chemokine CXCL12; Epidermal Growth Factor; Gene Expression Regulation, Neoplastic; GTP-Binding Protein alpha Subunits, Gi-Go; Humans; Male; Neoplasm Invasiveness; Oncogene Protein v-akt; Oxytocin; Phosphatidylinositol 3-Kinases; Phosphorylation; Prostate; Prostatic Neoplasms; rac1 GTP-Binding Protein; Transforming Growth Factor beta1

To measure the level of oxytocin in serum and prostate cancer (PCa) tissue and study its effect on the proliferation of PCa cells.. Oxytocin level in serum was significantly increased in PCa patients compared with the no-carcinoma individuals. Additionally, the levels of oxytocin and its receptor were also elevated in the PCa tissue. However, no significant difference existed among the PCa of various Gleason grades. Western blot analysis confirmed the previous results and revealed an increased expression level of APPL1.. The level of oxytocin in serum was measured by ELISA analysis. The expression of oxytocin and its receptor in prostate was analyzed by immunohistochemistry. The proliferation and apoptosis of PCa cells were assessed by the Cell Counting Kit 8 (CCK8) assay, cell cycle analysis and caspase3 activity analysis, respectively. Western blot analysis was used for the detection of PCNA, Caspase3 and APPL1 protein levels.. Serum and prostatic oxytocin levels are increased in the PCa subjects. Serum oxytocin level may be a biomarker for PCa in the future. Oxytocin increases PCa growth and APPL1 expression.

Topics: Aged; Apoptosis; Biomarkers, Tumor; Case-Control Studies; Cell Line, Tumor; Cell Proliferation; Humans; Immunohistochemistry; Male; Middle Aged; Neoplasm Staging; Odds Ratio; Oxytocin; Prostatic Neoplasms; Receptors, Oxytocin; Retrospective Studies; ROC Curve

It is known that oxytocin stimulates steroidogenesis in several organs by modulating activity of 3β-hydroxysteroid dehydrogenases (HSD3B) and steroid 5α-reductases (SRD5A). However, this has not been established in prostate cancer where these enzymes, key to local production of androgens, are increased. Analysis of both HSD3B and SRD5A activities using a live cell in situ colourimetric assay demonstrated that in PC-3 cells HSD3B activity was significantly increased by oxytocin whilst SRD5A activity was unchanged. This was confirmed in ELISA based assays of conversion of pregnenolone to progesterone and testosterone to dihydrotestosterone in cell lysates following treatment. In contrast, oxytocin significantly inhibited HSD3B activity in LNCaPs, but significantly increased activity of SRD5A, as confirmed by ELISA assays. Analysis of both cell lines by microarray and qRT-PCR determined that these changes were not due to altered gene transcription. This study demonstrates differential effects of oxytocin on the activities of key de novo steroidogenic enzymes in prostate cancer cells.

Topics: 3-Oxo-5-alpha-Steroid 4-Dehydrogenase; Cell Line, Tumor; Enzyme Activation; Humans; Male; Multienzyme Complexes; Neoplasm Proteins; Oxytocin; Progesterone Reductase; Prostatic Neoplasms; Steroid Isomerases

Cell- and receptor-specific regulation of cell migration by Gi/oα-proteins remains unknown in prostate cancer cells. In the present study, oxytocin (OXT) receptor was detected at the protein level in total cell lysates from C81 (an androgen-independent subline of LNCaP), DU145 and PC3 prostate cancer cells, but not in immortalized normal prostate luminal epithelial cells (RWPE1), and OXT-induced migration of PC3 cells. This effect of OXT has been shown to be mediated by Gi/oα-dependent signaling. Accordingly, OXT inhibited forskolin-induced luciferase activity in PC3 cells that were transfected with a luciferase reporter for cyclic AMP activity. Although mRNAs for all three Giα isoforms were present in PC3 cells, Giα2 was the most abundant isoform that was detected at the protein level. Pertussis toxin (PTx) inhibited the OXT-induced migration of PC3 cells. Ectopic expression of the PTx-resistant Giα2-C352G, but not wild-type Giα2, abolished this effect of PTx on OXT-induced cell migration. The Giα2-targeting siRNA was shown to specifically reduce Giα2 mRNA and protein in prostate cancer cells. The Giα2-targeting siRNA eliminated OXT-induced migration of PC3 cells. These data suggest that Giα2 plays an important role in the effects of OXT on PC3 cell migration. The Giα2-targeting siRNA also inhibited EGF-induced migration of PC3 and DU145 cells. Expression of the siRNA-resistant Giα2, but not wild type Giα2, restored the effects of EGF in PC3 cells transfected with the Giα2-targeting siRNA. In conclusion, Giα2 plays an essential role in OXT and EGF signaling to induce prostate cancer cell migration.

Topics: Animals; Cell Line, Tumor; Cell Movement; Epidermal Growth Factor; Gene Expression Regulation, Neoplastic; Gene Silencing; GTP-Binding Protein alpha Subunit, Gi2; Humans; Male; Oxytocin; Prostatic Neoplasms; Rats; Receptors, Oxytocin; RNA, Small Interfering

Expression of genes that encode oxytocin (OXT) and vasopressin (AVP) and their cognate receptors in normal and diseased prostates are only partially characterized. Reverse transcription and PCR were used to examine the expression of these genes in normal prostate epithelial and stromal cell lines, k-ras-transformed prostate epithelial cell lines, and in four prostate cancer cell lines. Secreted and cell-associated OXT peptide was measured by an enzyme immunoassay. OXT and its receptor (OXTR) were expressed in all eight prostate cell lines. Cell-associated OXT peptide was also found in all prostate epithelial cell lines except in DU145 cells. Neither AVP nor its cognate receptors (V1a receptor and V2 receptor) were expressed in any prostate cell line examined. These data point to the OXTR as the primary target of OXT and AVP, and suggest that OXT might be an autocrine/paracrine regulator in human prostate. We found that OXT induces the migration of PC3 and PC3M, but not DU145 prostate cancer cells. The effect of OXT is distinct from the epidermal growth factor (EGF)-induced migration of prostate cancer cells, in which ERK1/2 and EGF receptor kinase activities were required. When cells were pretreated with pertussis toxin, the effect of OXT, but not EGF, on cell migration was abolished. Pretreatment with the cyclic AMP analogue, 8-Br-cAMP, did not affect OXT-induced cell migration, which eliminated the nonspecific effect of pertussis toxin. We conclude that a Gi-dependent mechanism is involved in OXTR-mediated migration of prostate cancer cells, and indicates a role for OXTR in prostate cancer metastasis.

Topics: Blotting, Western; Cell Adhesion; Cell Movement; Cell Proliferation; Cells, Cultured; ErbB Receptors; GTP-Binding Protein alpha Subunits, Gi-Go; Humans; Male; Oxytocics; Oxytocin; Peptide Fragments; Pertussis Toxin; Prostatic Neoplasms; Receptors, Oxytocin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; Stromal Cells; Vasoconstrictor Agents; Vasopressins

Oxytocin (OT) is implicated in regulating prostate growth. OT concentrations are increased in benign, and decreased in malignant prostate disease. This study investigated whether the altered concentrations of OT present in prostate disease affect the proliferation of malignant and non-malignant human prostate cells.. The effects of varying concentrations of OT and gonadal steroids on cell proliferation of non-malignant prostatic epithelial (PrEC) and stromal (PrSC) cells and androgen dependent (LNCaP) and independent (PC-3) malignant cell lines were assessed.. OT (>0.5 nmol . L(-1)) had no effect on PrEC proliferation when cells were cultured alone. When co-cultured with PrSC and gonadal steroids, OT inhibited epithelial cell proliferation. OT inhibited PrSC proliferation, when cells were cultured alone. When PrSC were co-cultured in the presence of estrogen physiological concentrations of OT were inhibitory. No effect on cell proliferation was observed with higher concentrations of OT. OT did not affect the proliferation of malignant cell lines in the absence of androgens but, in the presence of testosterone, low concentrations of OT (<1 nmol . L(-1)) stimulated proliferation of PC-3 cells. Disruption of caveolae in the plasma membrane removed the inhibitory effect of OT on PrSC proliferation but did not affect the stimulatory effect of OT on PC-3 cells cultured in the presence of androgens.. Changes in prostatic concentrations of OT that occur with aging and malignant disease may act to facilitate cell proliferation. The localization of the OT receptor within the plasma membrane modulates OT's proliferative response in the prostate.

Topics: Aging; Androgens; Caveolae; Cell Line; Cell Line, Tumor; Cell Membrane; Cell Proliferation; Epithelial Cells; Humans; Male; Oxytocin; Prostate; Prostatic Hyperplasia; Prostatic Neoplasms; Receptors, Oxytocin; Testosterone

Topics: Data Interpretation, Statistical; Ejaculation; Humans; Male; Oxytocin; Prospective Studies; Prostatic Neoplasms; Sexual Behavior

Data on the presence of oxytocin receptors (OTR) within the prostate are still controversial and variable among different species. In the present study, OTR expression and localization has been investigated in human hyperplastic and neoplastic prostate at mRNA and protein levels using in situ hybridization (ISH) and immunohistochemistry (ICC) techniques, respectively. In all the cases studied, epithelial cells expressed OTR mRNA and protein. Interestingly, this expression was more intense in neoplastic epithelial cells compared to the hyperplastic ones. In order to determine whether OTR might mediate a biological effect of oxytocin (OT) in prostate cancer cells, OTR expression was studied by RT-PCR and immunofluorescence technique in the human androgen-independent prostate cancer cell line DU145. In addition, a possible heterotopic production of OT by DU145 cells was studied using RT-PCR. The data obtained showed that DU145 cells expressed OTR, whereas no OT mRNA was detected. When DU145 cells were treated with OT (100 nM) a significant inhibition of cell proliferation was observed, while co-incubation with the OT antagonist OTA (100 nm) abolished such an effect. The involvement of apoptosis in the OT effect contrasting cell proliferation was excluded by ISEL technique, which revealed a similar pattern of DNA fragmentation in either untreated or OT-treated cells. Altogether, the data indicate that the OT/OTR system could be involved in the control of prostate neoplastic pathology.

Topics: Cell Division; DNA Fragmentation; Humans; Male; Oxytocin; Prostate; Prostatic Neoplasms; Receptors, Oxytocin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Oxytocin has been implicated in the regulation of prostate growth. However, the cellular localisation of oxytocin in the normal and diseased human prostate is not known. Oxytocin, oxytocin-associated neurophysin and oxytocin receptor were detected by immunohistochemistry in tissues from patients undergoing routine prostatectomy and in normal human prostate epithelial and stromal cell lines. Western blot analysis detected a single band at 14 kDa with neurophysin antiserum and a 66-kDa band with oxytocin receptor antiserum in epithelial and stromal cell lines. Similar sized bands were also detected in extracts of hyperplastic and adenocarcinomic prostate tissues. Oxytocin, oxytocin-associated neurophysin and oxytocin receptor were present in stromal and epithelial cell lines and in tissue from patients with benign prostatic hyperplasia. The peptides were localised predominantly to the epithelial cells, although discrete areas of stromal staining were also observed. There was a significant difference in the intensity of oxytocin-staining between tissue displaying benign prostatic hyperplasia and invasive carcinoma, with less immunoreactivity being present in the malignant epithelial cells. Thus, oxytocin and its neurophysin and receptor are present in epithelial and stromal cells of the human prostate. Oxytocin expression is reduced with tumour progression and may provide a marker for invasive disease.

Topics: Adenocarcinoma; Blotting, Western; Cell Line; Humans; Immunohistochemistry; Male; Neurophysins; Oxytocin; Prostate; Prostatic Neoplasms; Receptors, Oxytocin; Stromal Cells

Vapreotide (RC-160), a somatostatin analog, was labeled with 99mTC by a direct method and also by using CPTA [1,4,8,11-tetraazacyclotetradecane] as a bifunctional chelating agent. The labeled compounds were evaluated in nude mice bearing experimental human prostate cancers. In these studies, 111In-DTPA-D-Phe-Octreotide (111In-DTPA-octreotide) served as a standard and 99mTc-oxytocin as a receptor-non-specific control. 99mTc-octreotide was also used. The 24 htumor uptake of 99mTc-RC-160 was nearly 400% higher, (p < 0.05), than that of 111In-DTPA-octreotide and diminished upon receptor blocking. In all tissues except the kidneys, the uptake of 99mTc-RC-160 was also higher than that of 111In-DTPA-octreotide. The uptake of 99mTc-RC-160 was influenced by the amount of peptide injected and the best tumor/muscle and tumor/blood ratios were obtained when only one micrograms of the peptide (200 Ci/mmol) was administered.

Topics: Animals; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Humans; Male; Mice; Mice, Nude; Octreotide; Oxytocin; Prostatic Neoplasms; Radionuclide Imaging; Receptors, Somatostatin; Somatostatin; Technetium Compounds; Tissue Distribution; Tumor Cells, Cultured