Upregulation of Oxytocin Receptor in the Hyperplastic Prostate

Background: The etiology of benign prostatic hyperplasia (BPH) is complex, both age and androgen are thought to be important. However, the failure of androgen blockade treatments suggests other paracrine/autocrine factors involved in BPH. Oxytocin was found to have a paracrine/autocrine role in prostate in recent years. The influence of BPH on prostatic oxytocin receptor (OTR) expression has never been studied. Material and methods: A testosterone-estradiol induced rat model of BPH was employed and human hyperplastic prostate specimens were harvested. Expressions of OTR, α1-adrenoreceptor subtypes and nitric oxide synthase isoforms were determined via real-time RT-PCR. OTR was further analyzed with Western-Blotting and histological examination. Subsequently, rat epithelial cells, human stromal cells and epithelial cells were cultured in vitro and treated with gradient concentrations of OT from 1 to 5 days. Cell proliferation was tested by Cell Counting Kit-8 and Flow Cytometry. Results: The rat BPH model was validated with significant increased prostate weight. H-E stain revealed a different histopathology between human and rat BPH. Masson's trichrome staining demonstrated that smooth muscle (SM) cells, epithelium cells and collagen fibers were simultaneously augmented in this rat BPH model and human BPH samples. OTR mainly localized in epithelium in rat prostate whereas it mainly localized in stroma in human prostate. OTR gene was upregulated 3.3-fold in rat BPH and 3.0-fold in human BPH, along with increased expression of 2.0-fold α1aARs and 3.0-fold eNOS for rat BPH and 5.0-fold α1aARs for human BPH. The expression of OTR protein was upregulated 1.4-fold in rat BPH and 3.9-fold in human BPH, respectively. Increased concentrations of exogenous OT can accelerate proliferation of rat epithelial cells and human stromal cells but has no impact on human epithelial cells in vitro. Flow Cytometry showed oxytocin could significantly increase G2/M period cell number. Conclusions: Our novel data demonstrates a significant and previously undocumented upregulation of OTR in both rat and human BPH. Moreover, exogenous OT accelerates proliferation of rat prostate epithelial cells and human prostate stromal cells. It is suggested OTR is involved in the development of BPH and OT regulatory system could be a potential new target for the BPH treatment.

[1]  I. McGregor,et al.  The role of the vasopressin V1A receptor in oxytocin modulation of methamphetamine primed reinstatement , 2018, Neuropharmacology.

[2]  Zhiguang Qiao,et al.  Oxytocin: its role in benign prostatic hyperplasia via the ERK pathway. , 2017, Clinical science.

[3]  K. Iwata,et al.  Oxytocin alleviates orofacial mechanical hypersensitivity associated with infraorbital nerve injury through vasopressin-1A receptors of the rat trigeminal ganglia , 2017, Pain.

[4]  T. Kallak,et al.  Oxytocin stimulates cell proliferation in vaginal cell line Vk2E6E7 , 2017, Post reproductive health.

[5]  Xinghuan Wang,et al.  Upregulation of Phosphodiesterase type 5 in the Hyperplastic Prostate , 2015, Scientific Reports.

[6]  K. Loughlin,et al.  Benign prostatic hyperplasia: epidemiology, economics and evaluation. , 2015, The Canadian journal of urology.

[7]  M. Oelke,et al.  EAU Guidelines on the Assessment of Non-neurogenic Male Lower Urinary Tract Symptoms including Benign Prostatic Obstruction. , 2015, European urology.

[8]  Qun Zhou,et al.  Oxytocin inhibits the activity of acid‐sensing ion channels through the vasopressin, V1A receptor in primary sensory neurons , 2014, British journal of pharmacology.

[9]  John J. Tyson,et al.  Irreversible Transitions, Bistability and Checkpoint Controls in the Eukaryotic Cell Cycle: A Systems-Level Understanding , 2013 .

[10]  I. Shin,et al.  Effects of Melandrium firmum methanolic extract on testosterone-induced benign prostatic hyperplasia in Wistar rats. , 2012, Asian journal of andrology.

[11]  H. Nicholson,et al.  Oxytocin--its role in male reproduction and new potential therapeutic uses. , 2006, Human reproduction update.

[12]  G. Forti,et al.  Identification, localization and functional in vitro and in vivo activity of oxytocin receptor in the rat penis. , 2005, The Journal of endocrinology.

[13]  S. Assinder,et al.  Oxytocin, oxytocin-associated neurophysin and the oxytocin receptor in the human prostate , 2004, Cell and Tissue Research.

[14]  H. Kajiyama,et al.  Oxytocin inhibits the progression of human ovarian carcinoma cells in vitro and in vivo , 2004, International journal of cancer.

[15]  C. Foster,et al.  Relationship between upregulated oestrogen receptors and expression of growth factors in cultured, human, prostatic stromal cells exposed to estradiol or dihydrotestosterone , 2004, Prostate Cancer and Prostatic Diseases.

[16]  N. Payet,et al.  Adrenal glomerulosa mitotic stimulation by posterior pituitary hormones , 1976, Cell and Tissue Research.

[17]  A. Sapino,et al.  Oxytocin inhibits proliferation of human breast cancer cell lines , 2004, Virchows Archiv.

[18]  A. Argiolas,et al.  Central oxytocinergic neurotransmission: a drug target for the therapy of psychogenic erectile dysfunction. , 2003, Current drug targets.

[19]  C. Breton,et al.  Oxytocin synthesis and oxytocin receptor expression by cell lines of human small cell carcinoma of the lung stimulate tumor growth through autocrine/paracrine signaling. , 2002, Cancer research.

[20]  G. Gimpl,et al.  The oxytocin receptor system: structure, function, and regulation. , 2001, Physiological reviews.

[21]  A. Sapino,et al.  Biological relevance of oxytocin and oxytocin receptors in cancer cells and primary tumors. , 2001, Annals of oncology : official journal of the European Society for Medical Oncology.

[22]  R. Ivell,et al.  The role of sex steroids in the oxytocin hormone system , 1999, Molecular and Cellular Endocrinology.

[23]  R. Roberts,et al.  Longitudinal prostate growth rates during 5 years in randomly selected community men 40 to 79 years old. , 1999, The Journal of urology.

[24]  H. Nicholson,et al.  Localization of oxytocin receptors in the human and macaque monkey male reproductive tracts: evidence for a physiological role of oxytocin in the male. , 1998, Molecular human reproduction.

[25]  H. Klocker,et al.  Human prostatic smooth muscle cells in culture: Estradiol enhances expression of smooth muscle cell‐specific markers , 1997, The Prostate.

[26]  R. Ivell,et al.  Oxytocin and oxytocin receptor expression in reproductive tissues of the male marmoset monkey. , 1997, Biology of reproduction.

[27]  G. Tsujimoto,et al.  Quantification and distribution of α1‐adrenoceptor subtype mRNAs in human prostate: comparison of benign hypertrophied tissue and non‐hypertrophied tissue , 1996, British journal of pharmacology.

[28]  K. Griffiths,et al.  The regulation of prostatic growth , 1996 .

[29]  H. Yamanaka,et al.  Endocrine environment of benign prostatic hyperplasia: prostate size and volume are correlated with serum estrogen concentration. , 1995, Scandinavian journal of urology and nephrology.

[30]  H. Nicholson,et al.  Oxytocin and prostatic function. , 1995, Advances in experimental medicine and biology.

[31]  D. Neal,et al.  Androgen and oestrogen responsiveness of stromal cells derived from the human hyperplastic prostate: oestrogen regulation of the androgen receptor. , 1994, The Journal of endocrinology.

[32]  A. Abramovici,et al.  Comparative study of experimentally induced benign and atypical hyperplasia in the ventral prostate of different rat strains. , 1994, Journal of andrology.

[33]  M. Caron,et al.  Identification, quantification, and localization of mRNA for three distinct alpha 1 adrenergic receptor subtypes in human prostate. , 1993, The Journal of urology.

[34]  K. Honda,et al.  Alpha 1-adrenoceptor subtype in the rat prostate is preferentially the alpha 1A type. , 1993, Japanese journal of pharmacology.

[35]  K. Mori,et al.  Structure and expression of a human oxytocin receptor , 1992, Nature.

[36]  Ž. Milićević,et al.  Stereologic analysis of ventral prostate of oxytocin-treated rats. , 1990, Archives of andrology.

[37]  G. Burford,et al.  Identification of oxytocin and vasopressin in the testis and in adrenal tissue , 1984, Regulatory Peptides.