Inhibitory effects of antagonists of growth hormone-releasing hormone on growth and invasiveness of PC3 human prostate cancer
Inhibitory effects of antagonists of growth hormone-releasing hormone on growth and invasiveness of PC3 human prostate cancer
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DOI：
10.1002/ijc.27716
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发表时间：
2013-02-15
影响因子：
6.4
通讯作者：
Bajo, Ana M.
中科院分区：
文献类型：
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作者：
Munoz-Moreno, Laura;Isabel Arenas, M.;Bajo, Ana M.
需要新的方法来治疗晚期前列腺癌。本研究通过评估在很大程度上导致前列腺癌进展的各种因素，确定了生长激素释放激素（GHRH）拮抗剂JMR-132和JV-1-38对PC 3肿瘤生长以及血管生成和转移的影响。将人PC 3雄激素非依赖性前列腺癌细胞皮下注射到裸鼠中。用JMR-132（10 μ g/天）或JV-1-38（20 μ g/天）处理持续41天。我们还评估了JMR-132和JV-1-38对PC-3细胞体外增殖、细胞粘附和迁移的影响。采用免疫印迹、逆转录聚合酶链反应、免疫组化、酶联免疫吸附试验（ELISA）和酶谱分析等方法检测GHRH受体及其剪接变异体、GHRH、血管内皮生长因子（VEGF）、缺氧诱导因子（HIF）-1 α、金属蛋白酶（MMPs）-2和-9、β-连环蛋白和E-钙粘蛋白的表达水平。GHRH拮抗剂在体外抑制PC-3细胞的增殖，并显著抑制PC-3肿瘤的生长。用这些类似物治疗后，我们发现GHRH受体表达增加，伴随着GHRH水平降低，VEGF和HIF-1 α表达降低，MMP-2和MMP-9活性形式减少，膜相关β-连环蛋白水平显著增加，E-钙粘蛋白显著下降。这些结果支持GHRH受体的阻断可以调节参与血管生成和转移的元件。因此，GHRH拮抗剂可以被认为是雄激素非依赖性前列腺癌治疗试验的合适候选药物。
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 mu g/day) or JV-1-38 (20 mu g/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)-1 alpha, metalloproteinases (MMPs) -2 and -9, beta-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-1 alpha expression and in active forms of MMP-2 and MMP-9, a significant increase in levels of membrane-associated beta-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.