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Inhibitory effects of antagonists of growth hormone‐releasing hormone on growth and invasiveness of PC3 human prostate cancer
Author(s) -
MuñozMoreno Laura,
Arenas M. Isabel,
Schally Andrew V.,
FernándezMartínez Ana B.,
Zarka Elías,
GonzálezSantander Marta,
Carmena María J.,
Vacas Eva,
Prieto Juan C.,
Bajo Ana M.
Publication year - 2012
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.27716
Subject(s) - angiogenesis , endocrinology , prostate cancer , medicine , vascular endothelial growth factor , metastasis , biology , prostate , receptor , cancer research , cancer , vegf receptors
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.