Inhibitory effects of antagonists of growth hormone-releasing hormone on growth and invasiveness of PC3 human prostate cancer.
New approaches are needed to the therapy of advanced prostate cancer. This study determined the effect of growth hormone-releasing hormone (GHRH) antagonists, JMR-132 and JV-1-38 on growth of PC3 tumors as well as on angiogenesis and metastasis through the evaluation of various factors that contribute largely to the progression of prostate cancer. Human PC3 androgen-independent prostate cancer cells were injected subcutaneously into nude mice. The treatment with JMR-132 (10 μg/day) or JV-1-38 (20 μg/day) lasted 41 days. We also evaluated the effects of JMR-132 and JV-1-38 on proliferation, cell adhesion and migration in PC-3 cells in vitro. Several techniques (Western blot, reverse transcription polymerase chain reaction, immunohistochemistry, ELISA and zymography) were used to evaluate the expression levels of GHRH receptors and its splice variants, GHRH, vascular endothelial growth factor (VEGF), hypoxia inducible factor (HIF)-1α, metalloproteinases (MMPs) -2 and -9, β-catenin and E-cadherin. GHRH antagonists suppressed the proliferation of PC-3 cells in vitro and significantly inhibited growth of PC3 tumors. After treatment with these analogues, we found an increase in expression of GHRH receptor accompanied by a decrease of GHRH levels, a reduction in both VEGF and HIF-1α expression and in active forms of MMP-2 and MMP-9, a significant increase in levels of membrane-associated β-catenin and a significant decline in E-cadherin. These results support that the blockade of GHRH receptors can modulate elements involved in angiogenesis and metastasis. Consequently, GHRH antagonists could be considered as suitable candidates for therapeutic trials in the management of androgen-independent prostate cancer.
Molecular Neuroendocrinology Unit, Department of Biochemistry and Molecular Biology, University of Alcalá, Alcalá de Henares, Spain.
Laura
L
Muñoz-Moreno
M Isabel
MI
Arenas
Andrew V
AV
Schally
Ana B
AB
Fernández-Martínez
Elías
E
Zarka
Marta
M
González-Santander
María J
MJ
Carmena
Eva
E
Vacas
Juan C
JC
Prieto
Ana M
AM
Bajo
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015820:Cadherins / Q000378:metabolism; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D013007:Growth Hormone-Releasing Hormone / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis / Q000188:drug therapy*; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011897:Random Allocation; D018013:Receptors, Neuropeptide / Q000378:metabolism; D018017:Receptors, Pituitary Hormone-Regulating Hormone / Q000378:metabolism; D017337:Sermorelin / Q000031:analogs & derivatives* / Q000494:pharmacology; D042442:Vascular Endothelial Growth Factors / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000378:metabolism
D000970:Antineoplastic Agents; D015820:Cadherins; 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)-; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C411623:JV 1-38; D018013:Receptors, Neuropeptide; D018017:Receptors, Pituitary Hormone-Regulating Hormone; D042442:Vascular Endothelial Growth Factors; D051176:beta Catenin; D017337:Sermorelin; D013007:Growth Hormone-Releasing Hormone; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; C048250:somatotropin releasing hormone receptor