Stratton M Suzanne, Greenstein Benjamin, Udayakumar Thirupandiyur S, Nagle Raymond B, Bowden G Timothy
Department of Radiation Oncology, Arizona Cancer Center, Tucson, Arizona 85724, USA.
Prostate. 2002 Sep 15;53(1):1-8. doi: 10.1002/pros.10123.
We have shown previously that interleukin (IL) -1 beta- and IL-6-induced promatrilysin expression is mediated by an indirect pathway that requires NF kappa B-dependent synthesis of IL-6 and STAT3 signaling. We now demonstrate that IL-1 beta-induced but not IL-6-induced promatrilysin expression can be blocked by androgens in the prostate carcinoma cell line LNCaP (lymph node-derived carcinoma cells of the prostate).
By using enzyme-linked immunosorbent assay analyses, promatrilysin was measured in LNCaP cells stimulated with IL-1 beta or IL-6 LNCaP-treated cells pretreated with testosterone. In addition, promatrilysin message was measured by using Northern analyses after IL-6-treated cells pretreated with testosterone.
In LNCaP treated with testosterone before IL-1 beta stimulation induced promatrilysin expression was completely abrogated. Furthermore, testosterone completely abrogated NF kappa B transactivation activity and induction of IL-6 protein expression and mRNA. Testosterone and 5 alpha-dihydrotestosterone did not have an inhibitory effect on IL-6-induced promatrilysin expression. Testosterone also had no effect on basal promatrilysin expression or basal NF kappa B transactivation activity.
From these data, we conclude that testosterone blocks IL-1 beta-induced promatrilysin expression by inhibition of NF kappa B transactivation activity, which in turn, blocks IL-6 expression. These data suggest a mechanism in vivo by which invasive and metastatic prostatic carcinoma cell clones refractory to hormone ablation therapy may develop after chemical or surgical castration. Furthermore, these data suggest that, perhaps, upstream targets such as the cytokines IL-1 beta and IL-6 may provide alternative drug targets for inhibiting prostate cancer progression.
我们之前已经表明，白细胞介素（IL）-1β和IL-6诱导的前基质溶素表达是由一条间接途径介导的，该途径需要NF-κB依赖的IL-6合成和STAT3信号传导。我们现在证明，在前列腺癌细胞系LNCaP（前列腺淋巴结衍生癌细胞）中，雄激素可阻断IL-1β诱导的而非IL-6诱导的前基质溶素表达。
通过酶联免疫吸附测定分析，在用IL-1β或IL-6刺激的LNCaP细胞以及用睾酮预处理的LNCaP处理细胞中测量前基质溶素。此外，在用睾酮预处理的IL-6处理细胞后，通过Northern分析测量前基质溶素信息。
在IL-1β刺激前用睾酮处理的LNCaP中，诱导的前基质溶素表达被完全消除。此外，睾酮完全消除了NF-κB反式激活活性以及IL-6蛋白表达和mRNA的诱导。睾酮和5α-二氢睾酮对IL-6诱导的前基质溶素表达没有抑制作用。睾酮对基础前基质溶素表达或基础NF-κB反式激活活性也没有影响。
从这些数据中，我们得出结论，睾酮通过抑制NF-κB反式激活活性来阻断IL-1β诱导的前基质溶素表达，这反过来又阻断了IL-6表达。这些数据提示了一种体内机制，通过该机制，化学或手术去势后，对激素消融治疗难治的侵袭性和转移性前列腺癌细胞克隆可能会出现。此外，这些数据表明，也许诸如细胞因子IL-1β和IL-6等上游靶点可能为抑制前列腺癌进展提供替代药物靶点。
