Degraff David J, Aguiar Adam A, Chen Qian, Adams Lisa K, Williams B Jill, Sikes Robert A
Am J Transl Res. 2010 Mar 6;2(2):200-8.
The insulin-like growth factor (IGF) axis is associated intimately with prostate cancer (PCa) development, growth, survival and metastasis. In particular, increased levels of IGFBP-2 expression are associated with advanced PCa, bone metastasis, and the development of castrate resistant PCa. Previously, we reported that androgen treatment decreased intracellular and extracellular IGFBP-2 in the androgen sensitive (AS) PCa cell line, LNCaP. Nonetheless, the mechanism by which androgen treatment decreases expression of IGFBP-2 is not clear. Since elevated IGFBP-2 is associated with a variety of advanced cancers, including PCa, coupled with the fact that hormone ablation is the customary treatment modality for advanced PCa, a complete understanding of the influence of androgens on IGFBP-2 expression is essential. Androgen treatment initially increased steady state IGFBP-2 mRNA levels in LNCaP cells. Extended androgen treatment on LNCaP resulted in a time-dependent decrease in both steady state IGFBP-2 mRNA and protein. Polysomal mRNA analysis showed no difference in IGFBP-2 association with a given fraction; however, Q-PCR revealed less IGFBP-2 mRNA in each androgen-treated fraction. In addition, there was an overall decrease in polysome mRNA after androgen treatment. Extracellular proteolysis of IGFBP-2 was prevented in the presence of serine protease inhibitors. These data indicate that androgen acts via multiple levels to down-regulate IGFBP-2 in LNCaP PCa cells.
胰岛素样生长因子（IGF）轴与前列腺癌（PCa）的发生、发展、存活及转移密切相关。特别是，IGFBP-2表达水平的升高与晚期PCa、骨转移以及去势抵抗性PCa的发生有关。此前，我们报道雄激素治疗可降低雄激素敏感（AS）PCa细胞系LNCaP细胞内和细胞外的IGFBP-2水平。然而，雄激素治疗降低IGFBP-2表达的机制尚不清楚。由于IGFBP-2水平升高与包括PCa在内的多种晚期癌症相关，加之激素消融是晚期PCa的常规治疗方式，因此全面了解雄激素对IGFBP-2表达的影响至关重要。雄激素治疗最初会增加LNCaP细胞中稳态IGFBP-2 mRNA水平。对LNCaP细胞进行延长的雄激素治疗会导致稳态IGFBP-2 mRNA和蛋白水平随时间下降。多核糖体mRNA分析显示IGFBP-2与特定组分的结合没有差异；然而，定量PCR显示每个雄激素处理组分中的IGFBP-2 mRNA较少。此外，雄激素处理后多核糖体mRNA总体减少。在丝氨酸蛋白酶抑制剂存在的情况下，IGFBP-2的细胞外蛋白水解受到抑制。这些数据表明雄激素通过多种水平作用于LNCaP PCa细胞以下调IGFBP-2。
