Castration-induced up-regulation of insulin-like growth factor binding protein-5 potentiates insulin-like growth factor-I activity and accelerates progression to androgen independence in prostate cancer models.
Castration-induced up-regulation of insulin-like growth factor binding protein-5 potentiates insulin-like growth factor-I activity and accelerates progression to androgen independence in prostate cancer models.
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发表时间：
2000-06
期刊：
影响因子：
11.2
通讯作者：
H. Miyake;M. Pollak;M. Gleave
中科院分区：
文献类型：
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作者：
H. Miyake;M. Pollak;M. Gleave
尽管胰岛素样生长因子结合蛋白-5(IGFBP-5)已被证明与前列腺癌的进展有关，但IGFBP-5在雄激素非依赖性进展中的功能仍未明确。在这里，我们展示了在去势诱导的小鼠雄激素依赖(AD)Shionogi肿瘤模型的退化和雄激素非依赖性(AI)进展过程中IGFBP-5的显著上调。为了分析IGFBP-5这些变化的功能意义，将IGFBP-5基因稳定导入人AD LNCaP前列腺癌细胞，与对照组相比，去势后高表达IGFBP-5的LNCaP肿瘤向雄激素依赖方向发展的速度明显加快。然后设计小鼠IGFBP-5反义寡核苷酸(ODN)，以剂量依赖和序列特异性的方式在体外降低Shionogi肿瘤细胞中IGFBP-5的表达。反义IGFBP-5 ODN可抑制Shionogi肿瘤细胞的生长，且呈时间和剂量依赖关系，外源性IGF-I可逆转该抑制作用。然而，当IGF-I活性被抗IGF-I抗体中和时，反义IGFBP-5 ODN处理对Shionogi肿瘤细胞的生长没有相加的抑制作用。反义IGFBP5ODN处理后，细胞周期中处于S+G2-M期的细胞数和丝裂原活化蛋白激酶活性降低，与Shionogi肿瘤细胞增殖率降低直接相关。在去势后全身应用反义IGFBP-5 ODN治疗Shionogi肿瘤的小鼠，显著延缓了进展到雄激素非依赖性的时间，并抑制了AI复发肿瘤的生长。这些发现表明，去势后上调IGFBP-5有助于增强IGF的生物活性，并增加前列腺癌对雄激素撤除的反应可以通过针对IGF信号转导的反义IGFBP-5 ODN治疗等策略来增强的可能性。
Although insulin-like growth factor binding protein-5 (IGFBP-5) has been shown to be implicated in prostate cancer progression, the functional role of IGFBP-5 in progression to androgen-independence remains largely undefined. Here, we demonstrate substantial up-regulation of IGFBP-5 during castration-induced regression and androgen-independent (AI) progression in the mouse androgen-dependent (AD) Shionogi tumor model. To analyze the functional significance of these changes in IGFBP-5, human AD LNCaP prostate cancer cells were stably transfected with IGFBP-5 gene, and IGFBP-5-overexpressing LNCaP tumors progressed significantly faster to androgen independence after castration compared with controls. Antisense mouse IGFBP-5 oligodeoxynucleotides (ODNs) were then designed that reduced IGFBP-5 expression in Shionogi tumor cells in vitro in a dose-dependent and sequence-specific manner. Growth of Shionogi tumor cells was inhibited by antisense IGFBP-5 ODN treatment in a time- and dose-dependent manner, which could be reversed by exogenous IGF-I. However, antisense IGFBP-5 ODN treatment had no additive inhibitory effect on Shionogi tumor cell growth when IGF-I activity was neutralized by anti-IGF-I antibody. Antisense IGFBP-5 ODN treatment resulted in decreased mitogen-activated protein kinase activity and number of cells in the S + G2-M phases of the cell cycle that directly correlated with reduced proliferation rate of Shionogi tumor cells. Systemic administration of antisense IGFBP-5 ODN in mice bearing Shionogi tumors after castration significantly delayed time to progression to androgen independence and inhibited growth of AI recurrent tumors. These findings suggest that up-regulation of IGFBP-5 after castration serves to enhance IGF bioactivity and raise the possibility that the response of prostate cancer to androgen withdrawal can be enhanced by strategies, such as antisense IGFBP-5 ODN therapy, that target IGF signal transduction.