Identification of EP4 as a potential target for the treatment of castration-resistant prostate cancer using a novel xenograft model.

More effective therapeutic approaches for castration-resistant prostate cancer (CRPC) are urgently needed, thus reinforcing the need to understand how prostate tumors progress to castration resistance. We have established a novel mouse xenograft model of prostate cancer, KUCaP-2, which expresses the wild-type androgen receptor (AR) and which produces the prostate-specific antigen (PSA). In this model, tumors regress soon after castration, but then reproducibly restore their ability to proliferate after 1 to 2 months without AR mutation, mimicking the clinical behavior of CRPC. In the present study, we used this model to identify novel therapeutic targets for CRPC. Evaluating tumor tissues at various stages by gene expression profiling, we discovered that the prostaglandin E receptor EP4 subtype (EP4) was significantly upregulated during progression to castration resistance. Immunohistochemical results of human prostate cancer tissues confirmed that EP4 expression was higher in CRPC compared with hormone-naïve prostate cancer. Ectopic overexpression of EP4 in LNCaP cells (LNCaP-EP4 cells) drove proliferation and PSA production in the absence of androgen supplementation in vitro and in vivo. Androgen-independent proliferation of LNCaP-EP4 cells was suppressed when AR expression was attenuated by RNA interference. Treatment of LNCaP-EP4 cells with a specific EP4 antagonist, ONO-AE3-208, decreased intracellular cyclic AMP levels, suppressed PSA production in vitro, and inhibited castration-resistant growth of LNCaP-EP4 or KUCaP-2 tumors in vivo. Our findings reveal that EP4 overexpression, via AR activation, supports an important mechanism for castration-resistant progression of prostate cancer. Furthermore, they prompt further evaluation of EP4 antagonists as a novel therapeutic modality to treat CRPC.

[1]  T. Guthrie,et al.  Prostate cancer. , 2020, American family physician.

[2]  P. Foubert,et al.  Integrin α4β1 signaling is required for lymphangiogenesis and tumor metastasis (Cancer Research (2010) 70, (3042-51) DOI , 2010 .

[3]  W. Lu,et al.  Tumor site-specific silencing of NF-κB p65 by targeted hollow gold nanosphere-mediated photothermal transfection (Cancer Research (2010) 70, (3177-3188) DOI: 10.1158/0008-5472.CAN-09-3379) , 2010 .

[4]  T. Schall,et al.  Tumor and Stem Cell Biology Cancer Research The Chemokine Receptor CXCR 7 Is Highly Expressed in Human Glioma Cells and Mediates Antiapoptotic Effects , 2010 .

[5]  J. F. Burrows,et al.  The deubiquitinating enzyme USP17 is highly expressed in tumor biopsies, is cell cycle regulated, and is required for G1-S progression. , 2010, Cancer research.

[6]  M. Kloor,et al.  Somatic hypermethylation of MSH2 is a frequent event in Lynch Syndrome colorectal cancers. , 2010, Cancer research.

[7]  A. Muotri,et al.  Coordination of centrosome homeostasis and DNA repair is intact in MCF-7 and disrupted in MDA-MB 231 breast cancer cells. , 2010, Cancer research.

[8]  J. Vincent,et al.  5-Fluorouracil selectively kills tumor-associated myeloid-derived suppressor cells resulting in enhanced T cell-dependent antitumor immunity. , 2010, Cancer research.

[9]  R. Hoffman,et al.  The effect of CXCL12 processing on CD34+ cell migration in myeloproliferative neoplasms. , 2010, Cancer research.

[10]  Chris T. Harvey,et al.  ID1 enhances docetaxel cytotoxicity in prostate cancer cells through inhibition of p21. , 2010, Cancer research.

[11]  J. Heath,et al.  Signal transducers and activators of transcription-3 binding to the fibroblast growth factor receptor is activated by receptor amplification. , 2010, Cancer research.

[12]  C. Croce,et al.  Oncogenic role of miR-483-3p at the IGF2/483 locus. , 2010, Cancer research.

[13]  P. Fisher,et al.  Molecular mechanism of chemoresistance by astrocyte elevated gene-1. , 2010, Cancer research.

[14]  Jing Ma,et al.  Immunohistochemical expression of BRCA1 and lethal prostate cancer. , 2010, Cancer research.

[15]  G. Mills,et al.  Mammalian target of rapamycin activator RHEB is frequently overexpressed in human carcinomas and is critical and sufficient for skin epithelial carcinogenesis. , 2010, Cancer research.

[16]  H. Kung,et al.  Aberrant activation of the androgen receptor by NF-kappaB2/p52 in prostate cancer cells. , 2010, Cancer research.

[17]  J. Chien,et al.  Downregulation of HtrA1 promotes resistance to anoikis and peritoneal dissemination of ovarian cancer cells. , 2010, Cancer research.

[18]  Wei Lu,et al.  Tumor Site–Specific Silencing ofNF-κB p65by Targeted Hollow Gold Nanosphere–Mediated Photothermal Transfection , 2010, Cancer Research.

[19]  O. Ogawa,et al.  Antiandrogen withdrawal syndrome and alternative antiandrogen therapy associated with the W741C mutant androgen receptor in a novel prostate cancer xenograft , 2010, The Prostate.

[20]  Clifford A. Meyer,et al.  Androgen Receptor Regulates a Distinct Transcription Program in Androgen-Independent Prostate Cancer , 2009, Cell.

[21]  Shalini Jain,et al.  Prostaglandin E2 regulates tumor angiogenesis in prostate cancer. , 2008, Cancer research.

[22]  R. Klein,et al.  Prostaglandin E2 induces vascular endothelial growth factor secretion in prostate cancer cells through EP2 receptor‐mediated cAMP pathway , 2007, Molecular carcinogenesis.

[23]  N. Kinukawa,et al.  Increased Akt and phosphorylated Akt expression are associated with malignant biological features of prostate cancer in Japanese men , 2007, BJU international.

[24]  O. Ogawa,et al.  Roles of androgen-dependent and -independent activation of signal transduction pathways for cell proliferation of prostate cancer cells , 2007, Expert review of endocrinology & metabolism.

[25]  S. Narumiya,et al.  Prostaglandin E Receptors* , 2007, Journal of Biological Chemistry.

[26]  Jianfeng Xu,et al.  Inflammation in prostate carcinogenesis , 2007, Nature Reviews Cancer.

[27]  T. Yamasaki,et al.  Requirement of androgen-dependent activation of protein kinase Czeta for androgen-dependent cell proliferation in LNCaP Cells and its roles in transition to androgen-independent cells. , 2006, Molecular endocrinology.

[28]  O. Kallioniemi,et al.  TMPRSS2 fusions with oncogenic ETS factors in prostate cancer involve unbalanced genomic rearrangements and are associated with HDAC1 and epigenetic reprogramming. , 2006, Cancer research.

[29]  D. Carbone,et al.  Host and direct antitumor effects and profound reduction in tumor metastasis with selective EP4 receptor antagonism. , 2006, Cancer research.

[30]  A. C. Williams,et al.  Mediators of PGE2 synthesis and signalling downstream of COX-2 represent potential targets for the prevention/treatment of colorectal cancer. , 2006, Biochimica et biophysica acta.

[31]  J. Manola,et al.  Celecoxib versus placebo for men with prostate cancer and a rising serum prostate-specific antigen after radical prostatectomy and/or radiation therapy. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[32]  A. Chokkalingam,et al.  Prostate cancer epidemiology. , 2006, Frontiers in bioscience : a journal and virtual library.

[33]  A. C. Williams,et al.  Increased EP4 receptor expression in colorectal cancer progression promotes cell growth and anchorage independence. , 2006, Cancer research.

[34]  G. Jenster,et al.  The human PC346 xenograft and cell line panel: a model system for prostate cancer progression. , 2006, European urology.

[35]  O. Ogawa,et al.  Antiandrogen bicalutamide promotes tumor growth in a novel androgen-dependent prostate cancer xenograft model derived from a bicalutamide-treated patient. , 2005, Cancer research.

[36]  T. Dang,et al.  Targeting Cyclooxygenase-2 in Recurrent Non–Small Cell Lung Cancer: A Phase II Trial of Celecoxib and Docetaxel , 2005, Clinical Cancer Research.

[37]  N. Kinukawa,et al.  Androgen receptor, Ki67, and p53 expression in radical prostatectomy specimens predict treatment failure in Japanese population. , 2005, Urology.

[38]  P. Casey,et al.  Androgen Receptor Activation by Gs Signaling in Prostate Cancer Cells* , 2005, Journal of Biological Chemistry.

[39]  D. Ghosh,et al.  Androgen-Independent Prostate Cancer Is a Heterogeneous Group of Diseases , 2004, Cancer Research.

[40]  C. Tangen,et al.  Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. , 2004, The New England journal of medicine.

[41]  M. Hull,et al.  Prostaglandin EP receptors: targets for treatment and prevention of colorectal cancer? , 2004, Molecular cancer therapeutics.

[42]  Y. Niitsu.  A ride on the ferrous wheel , 2004, Cancer biology & therapy.

[43]  J. Lewin,et al.  Suppression of prostate carcinogenesis by dietary supplementation of celecoxib in transgenic adenocarcinoma of the mouse prostate model. , 2004, Cancer research.

[44]  S. Balk,et al.  Androgen receptor: A key molecule in the progression of prostate cancer to hormone independence , 2004, Journal of cellular biochemistry.

[45]  E. Platz,et al.  Epidemiology of inflammation and prostate cancer. , 2004, The Journal of urology.

[46]  A. Aprikian,et al.  Prostate cancer and use of nonsteroidal anti-inflammatory drugs: systematic review and meta-analysis , 2004, British Journal of Cancer.

[47]  Chawnshang Chang,et al.  Expression and Degradation of Androgen Receptor: Mechanism and Clinical Implication , 2003 .

[48]  S. Narumiya,et al.  Prostaglandin E2–EP4 signaling initiates skin immune responses by promoting migration and maturation of Langerhans cells , 2003, Nature Medicine.

[49]  A. Levine,et al.  Prostaglandin E2 Induces Hypoxia-inducible Factor-1α Stabilization and Nuclear Localization in a Human Prostate Cancer Cell Line* , 2002, The Journal of Biological Chemistry.

[50]  C Michael Stein,et al.  COX-2 selective non-steroidal anti-inflammatory drugs and risk of serious coronary heart disease , 2002, The Lancet.

[51]  D. Feldman,et al.  The development of androgen-independent prostate cancer , 2001, Nature Reviews Cancer.

[52]  S. Narumiya,et al.  Acceleration of intestinal polyposis through prostaglandin receptor EP2 in ApcΔ716 knockout mice , 2001, Nature Medicine.

[53]  F. S. French,et al.  Androgen receptor stabilization in recurrent prostate cancer is associated with hypersensitivity to low androgen. , 2001, Cancer research.

[54]  A. Belldegrun,et al.  Evidence for clonal outgrowth of androgen-independent prostate cancer cells from androgen-dependent tumors through a two-step process. , 1999, Cancer research.

[55]  K. A. Klein,et al.  Progression of metastatic human prostate cancer to androgen independence in immunodeficient SCID mice , 1997, Nature Medicine.

[56]  Bruno C. Hancock,et al.  Suppression of Intestinal Polyposis in Apc Δ716 Knockout Mice by Inhibition of Cyclooxygenase 2 (COX-2) , 1996, Cell.

[57]  S. Schwartz,et al.  CWR22: the first human prostate cancer xenograft with strongly androgen-dependent and relapsed strains both in vivo and in soft agar. , 1996, Cancer research.

[58]  R L Vessella,et al.  Characterization of a novel androgen-sensitive, prostate-specific antigen-producing prostatic carcinoma xenograft: LuCaP 23. , 1996, Clinical cancer research : an official journal of the American Association for Cancer Research.

[59]  K. Metters,et al.  Cloning, functional expression, and characterization of the human prostaglandin E2 receptor EP2 subtype. , 1994, The Journal of biological chemistry.

[60]  M. Gleave,et al.  Serum prostate specific antigen levels in mice bearing human prostate LNCaP tumors are determined by tumor volume and endocrine and growth factors. , 1992, Cancer research.

[61]  J. Chien,et al.  Downregulation of HtrA 1 Promotes Resistance to Anoikis and Peritoneal Dissemination of Ovarian Cancer Cells , 2010 .

[62]  J. F. Burrows,et al.  Tumor and Stem Cell Biology Cancer Research The Deubiquitinating Enzyme USP 17 Is Highly Expressed in Tumor Biopsies , Is Cell Cycle Regulated , and Is Required for G 1S Progression , 2010 .

[63]  S. Narumiya,et al.  The roles of prostanoids in infection and sickness behaviors , 2008, Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy.

[64]  R. Lieberman.  Chemoprevention of Prostate Cancer: Current Status and Future Directions , 2004, Cancer and Metastasis Reviews.

[65]  R. Vessella,et al.  Molecular determinants of resistance to antiandrogen therapy , 2004, Nature Medicine.

[66]  Chawnshang Chang,et al.  Endocrine mechanisms of disease: Expression and degradation of androgen receptor: mechanism and clinical implication. , 2003, The Journal of clinical endocrinology and metabolism.

[67]  S. Narumiya,et al.  Involvement of prostaglandin E receptor subtype EP(4) in colon carcinogenesis. , 2002, Cancer research.

[68]  H. Gaylord,et al.  AMERICAN ASSOCIATION FOR CANCER RESEARCH. , 1913, California state journal of medicine.