title: Anti-proliferative and pro-apoptotic effects of GHRH antagonists in prostate cancer.
abstract: Growth hormone-releasing hormone (GHRH) and its receptors have been implicated in the progression of various tumors. In vitro and in vivo studies have demonstrated that GHRH antagonists inhibit the growth of several cancers. GHRH antagonists, JMR-132 and JV-1-38 inhibit the growth of androgen-independent prostate tumors. Here we investigated the involvement of GHRH antagonists in proliferative and apoptotic processes. We used non-tumoral RWPE-1 and tumoral LNCaP and PC3 human prostatic epithelial cells, as well as an experimental model of human tumor PC3 cells. We evaluated the effects of JMR-132 and JV-1-38 antagonists on cell viability and proliferation in the three cell lines by means of MTT and BrdU assays, respectively, as well as on cell cycle and apoptotic process in PC3 cells. The expression levels of PCNA, p53, p21, CD44, Cyclin D1, c-myc, Bax and Bcl2 were determined in both in vivo and in vitro models by means of Western-blot and RT-PCR. GHRH antagonists suppressed cell proliferation and decreased the levels of the proliferation marker, PCNA, in the three cell lines and in PC3 tumor. GHRH antagonists led to an increase of cells in S-phase and a decrease in G1 and G2/M phases, and induced S-phase arrest and increase of apoptotic cells. The effects of GHRH-antagonists on cell cycle could be due to the changes observed in the expression of p21, p53, Bax, Bcl2, CD44, Cyclin D1, c-myc and caspase 3. Present results confirm and extend the role of GHRH antagonists as anti-proliferative and pro-apoptotic molecules in prostate cancer.
authors.affiliation: Department of Systems Biology, Unit of Biochemistry and Molecular Biology, University of Alcalá, Alcalá de Henares, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Muñoz-Moreno
authors.affiliation: Department of Biomedicine and Biotechnology, Unit of Cell Biology, University of Alcalá, Alcalá de Henares, Spain.
authors.forename: Maria Isabel
authors.initials: MI
authors.lastname: Arenas
authors.affiliation: Department of Systems Biology, Unit of Biochemistry and Molecular Biology, University of Alcalá, Alcalá de Henares, Spain.
authors.forename: María J
authors.initials: MJ
authors.lastname: Carmena
authors.affiliation: Veterans Administration Medical Center and South Florida Veterans Affairs Foundation for Research and Education, Miami, FL, USA.|Departments of Pathology and Medicine, Division of Oncology and Hematology, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: Andrew V
authors.initials: AV
authors.lastname: Schally
authors.affiliation: Department of Surgery and Medical and Social Sciences, University of Alcalá, Alcalá de Henares, Spain.|Department of Urology, Príncipe de Asturias Hospital, Alcalá de Henares, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Sánchez-Chapado
authors.affiliation: Department of Systems Biology, Unit of Biochemistry and Molecular Biology, University of Alcalá, Alcalá de Henares, Spain.
authors.forename: Juan C
authors.initials: JC
authors.lastname: Prieto
authors.affiliation: Department of Systems Biology, Unit of Biochemistry and Molecular Biology, University of Alcalá, Alcalá de Henares, Spain.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Bajo
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D013007:Growth Hormone-Releasing Hormone / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D011471:Prostatic Neoplasms / Q000473:pathology*; D017337:Sermorelin / Q000031:analogs & derivatives / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C534070:GHRH(1-29)NH2, PhAcTyr(1)-Arg(2)-P(H)e(4-CL)(6)-Ala(8)-Tyr(Me)(10)-His(11)-Abu(15)-His(20)-Nle(27)-Arg(28)-HLCr(29)-; C411623:JV 1-38; D017337:Sermorelin; D013007:Growth Hormone-Releasing Hormone
keywords: GHRH; GHRH antagonists; apoptosis; cell proliferation; prostate cancer therapy