Mechanisms of prostate atrophy after LHRH antagonist cetrorelix injection: An experimental study in a rat model of benign prostatic hyperplasia

Abstract

In the present study, we investigated the roles of TGF-β signaling pathway in a rat benign prostatic hyperplasia (BPH) model treated with cetrorelix. TGF-β1 and c-Myc expression were measured by qRT-PCR and Western blotting in the proximal and distal region of ventral prostatic lobes, respectively. We observed that treatment with cetrorelix led to a significant reduction of ventral prostate weight in a dose-dependent manner. In the proximal region, after cetrorelix treatment, the expression of TGF-β1 was dramatically increased (P<0.05), while the expression of c-Myc was significantly decreased (P<0.05). In comparison with the control group, the cetrorelix groups had more TUNEL-positive cells. Our findings strongly suggest that the TGF-β signaling pathway may be one of the major causes responsible for prostate volume reduction in BPH rats after cetrorelix treatment.

Keywords

benign prostatic hyperplasia / LHRH / transforming growth factor-β

References

[1] RickF.G., SchallyA.V., BlockN.L., et al.. LHRH antagonist cetrorelix reduces prostate size and gene expression of proinflammatory cytokines and growth factors in a rat model of benign prostatic hyperplasia. Prostate, 2011, 71(7): 736-747

[2] HokeG.P., McWilliamsG.W.. Epidemiology of benign prostatic hyperplasia and comorbidities in racial and ethnic minority populations. Am J Med, 2008, 121(8Suppl2): S3-S10

[3] UntergasserG., MadersbacherS., BergerP.. Benign prostatic hyperplasia: age-related tissue-remodeling. Exp Gerontol, 2005, 40(3): 121-128

[4] LuciaM.S., LambertJ.R.. Growth factors in benign prostatic hyperplasia: basic science implications. Curr Urol Rep, 2008, 9(4): 272-278

[5] EatonC.L.. Aetiology and pathogenesis of benign prostatic hyperplasia. Curr Opin Urol, 2003, 13(1): 7-10

[6] CuligZ., HobischA., CronauerM.V., et al.. Regulation of prostatic growth and function by peptide growth factors. Prostate, 1996, 28(6): 392-405

[7] DebruyneF., TzvetkovM., AltaracS., et al.. Dose-ranging study of the luteinizing hormone-releasing hormone receptor antagonist cetrorelix pamoate in the treatment of patients with symptomatic benign prostatic hyperplasia. Urology, 2010, 76(4): 927-933

[8] Comaru-SchallyA.M., BrannanW., SchallyA.V., et al.. Efficacy and safety of luteinizing hormone-releasing hormone antagonist cetrorelix in the treatment of symptomatic benign prostatic hyperplasia. J Clin Endocrinol Metab, 1998, 83(11): 3826-3831

[9] DebruyneF., GresA.A., ArustamovD.L.. Placebo-controlled dose-ranging phase 2 study of subcutaneously administered LHRH antagonist cetrorelix in patients with symptomatic benign prostatic hyperplasia. Eur Urol, 2008, 54(1): 170-177

[10] LeporH.. The role of gonadotropin-releasing hormone antagonists for the treatment of benign prostatic hyperplasia. Rev Urol, 2006, 8(4): 183-189

[11] EngelJ.B., SchallyA.V.. Drug Insight: clinical use of agonists and antagonists of luteinizing-hormone-releasing hormone. Nat Clin Pract Endocrinol Metab, 2007, 3(2): 157-167

[12] SiejkaA., SchallyA.V., BlockN.L., et al.. Mechanisms of inhibition of human benign prostatic hyperplasia in vitro by the luteinizing hormone-releasing hormone antagonist cetrorelix. BJU Int, 2010, 106(9): 1382-1388

[13] RozsaB., NadjiM., SchallyA.V., et al.. Receptors for luteinizing hormone-releasing hormone (LHRH) in benign prostatic hyperplasia (BPH) as potential molecular targets for therapy with LHRH antagonist cetrorelix. Prostate, 2011, 71(5): 445-452

[14] LeeC., SintichS.M., MathewsE.P., et al.. Transforming growth factor-beta in benign and malignant prostate. Prostate, 1999, 39(4): 285-290

[15] HuangX., LeeC.. Regulation of stromal proliferation, growth arrest, differentiation and apoptosis in benign prostatic hyperplasia by TGF-beta. Front Biosci, 2003, 8: s 740-s749

[16] BrodinG., ten DijkeP., FunaK., et al.. Increased smad expression and activation are associated with apoptosis in normal and malignant prostate after castration. Cancer Res, 1999, 59(11): 2731-2738

[17] LandstromM., EklovS., ColosettiP., et al.. Estrogen induces apoptosis in a rat prostatic adenocarcinoma: association with an increased expression of TGF-beta 1 and its type-I and type-II receptors. I Int J Cancer, 1996, 67(4): 573-579

[18] WarnerB.J., BlainS.W., SeoaneJ., et al.. Myc down-regulation by transforming growth factor beta required for activation of the p15(Ink4b) G(1) arrest pathway. Mol Cell Biol, 1999, 19(9): 5913-5922

[19] YagiK., FuruhashiM., AokiH., et al.. c-myc is a downstream target of the Smad pathway. J Biol Chem, 2002, 277(1): 854-861

[20] ScolnikM.D., ServadioC., AbramoviciA.. Comparative study of experimentally induced benign and atypical hyperplasia in the ventral prostate of different rat strains. J Androl, 1994, 15(4): 287-297

[21] HorvathJ.E., TollerG.L., SchallyA.V., et al.. Effect of long-term treatment with low doses of the LHRH antagonist Cetrorelix on pituitary receptors for LHRH and gonadal axis in male and female rats. Proc Natl Acad Sci USA, 2004, 101(14): 4996-5001

[22] TsujimuraA., KoikawaY., SalmS., et al.. Proximal location of mouse prostate epithelial stem cells: a model of prostatic homeostasis. J Cell Biol, 2002, 157(7): 1257-1265

[23] TievaA., BerghA., DamberJ.E.. The clinical implications of the difference between castration, gonadotrophin releasing-hormone (GnRH) antagonists and agonist treatment on the morphology and expression of GnRH receptors in the rat ventral prostate. BJU Int, 2003, 91(3): 227-233

[24] KramerG., SteinerG.E., HandisuryaA., et al.. Increased expression of lymphocyte-derived cytokines in benign hyperplastic prostate tissue, identification of the producing cell types, and effect of differentially expressed cytokines on stromal cell proliferation. Prostate, 2002, 52(1): 43-58

[25] LiX., WangY., Sharif-AfsharA.R., et al.. Urothelial trans-differentiation to prostate epithelia is mediated by paracrine TGF-beta signaling. Differentiation, 2009, 77(1): 95-102

[26] SintichS.M., LammM.L., SensibarJ.A., et al.. Transforming growth factor-beta1-induced proliferation of the prostate cancer cell line, TSU-Pr1: the role of platelet-derived growth factor. Endocrinology, 1999, 140(8): 3411-3415

[27] XiL., HuW., MengL., et al.. Dysregulation of the TGF-beta postreceptor signaling pathway in cell lines derived from primary or metastatic ovarian cancer. J Huazhong Univ Sci Technolog [Med Sci], 2004, 24(1): 62-65

[28] LeeK.Y., BaeS.C.. TGF-beta-dependent cell growth arrest and apoptosis. J Biochem Mol Biol, 2002, 35(1): 47-53

[29] NemethJ.A., SensibarJ.A., WhiteR.R., et al.. Prostatic ductal system in rats: tissue-specific expression and regional variation in stromal distribution of transforming growth factor-beta 1. Prostate, 1997, 33(1): 64-71

[30] MaQ.J., GuX.Q., CaoX., et al.. Effect of beta radiation on TGF-beta1 and bFGF expression in hyperplastic prostatic tissues. Asian J Androl, 2005, 7(1): 49-54

[31] KlinglerH.C., BretlandA.J., ReidS.V., et al.. Regulation of prostatic stromal cell growth and function by transforming growth factor beta (TGFbeta). Prostate, 1999, 41(2): 110-120

[32] HsingA.Y., KadomatsuK., BonhamM.J., et al.. Regulation of apoptosis induced by transforming growth factor-beta1 in nontumorigenic rat prostatic epithelial cell lines. Cancer Res, 1996, 56(22): 5146-5149

[33] PelengarisS., KhanM.. The many faces of c-MYC. Arch Biochem Biophys, 2003, 416(2): 129-136

[34] EilersM.. Control of cell proliferation by Myc family genes. Mol Cells, 1999, 9(1): 1-6

[35] AmatiB.. Integrating Myc and TGF-beta signalling in cell-cycle control. Nat Cell Biol, 2001, 3(5): E112-113

[36] GartelA.L., ShchorsK.. Mechanisms of c-myc-mediated transcriptional repression of growth arrest genes. Exp Cell Res, 2003, 283(1): 17-21

[37] PelloO.M., De PizzolM., MiroloM., et al.. Role of c-MYC in alternative activation of human macrophages and tumor-associated macrophage biology. Blood, 2012, 119(2): 411-421

[38] KawakamiY., KubotaN., EkuniN., et al.. Tumor-suppressive lipoxygenases inhibit the expression of c-myc mRNA coding region determinant-binding protein/ insulin-like growth factor II mRNA-binding protein 1 in human prostate carcinoma PC-3 cells. Biosci Biotechnol Biochem, 2009, 73(8): 1811-1817

[39] WangH., MannavaS., GrachtchoukV., et al.. c-Myc depletion inhibits proliferation of human tumor cells at various stages of the cell cycle. Oncogene, 2008, 27(13): 1905-1915

[40] DaiW., ChenH., YuR., et al.. Effects of cadmium on telomerase activity, expressions of TERT, c-myc and P53, and apoptosis of rat hepatocytes. J Huazhong Univ Sci Technolog [Med Sci], 2010, 30(6): 709-713

[41] HerzingerT., WolfD.A., EickD., et al.. The pRb-related protein p130 is a possible effector of transforming growth factor beta 1 induced cell cycle arrest in keratinocytes. Oncogene, 1995, 10(11): 2079-2084

[42] AlexandrowM.G., KawabataM., AakreM., et al.. Overexpression of the c-Myc oncoprotein blocks the growth-inhibitory response but is required for the mitogenic effects of transforming growth factor beta 1. Proc Natl Acad Sci USA, 1995, 92(8): 3239-3243

[43] ClaassenG.F., HannS.R.. A role for transcriptional repression of p21CIP1 by c-Myc in overcoming transforming growth factor beta-induced cell-cycle arrest. Proc Natl Acad Sci USA, 2000, 97(17): 9498-9503

[44] KidderB.L., YangJ., PalmerS.. Stat3 and c-Myc genome-wide promoter occupancy in embryonic stem cells. PLoS One, 2008, 3(12): e3932

[45] DongJ., SutorS., JiangG., et al.. c-Myc regulates self-renewal in bronchoalveolar stem cells. PLoS One, 2011, 6(8): e23707