Kim J H, Tanabe T, Chodak G W, Rukstalis D B
University of Chicago Hospital, Section of Urology, IL 60637, USA.
Anticancer Res. 1995 Jul-Aug;15(4):1429-34.
Components of malignant invasion, namely cellular adhesion, motility, and proteolytic capability provide potential sites of pharmacological intervention for malignancy. In this study, a series of experiments were performed to examine the effects of N-(4-hydroxyphenyl) retinamide (4-HPR, Fenretinide) on cellular adhesion, motility and proteolytic activity of established prostate cancer cell lines, TSU-PR 1 and PC-3. Radioadhesion study showed that the treatment of TSU-PR 1 and PC-3 cells with 10(-6) M of 4-HPR resulted in a 32% and 37% reduction (p < 0.05), respectively, in the cellular adhesion to the matrigel extract. Radiomigration assay also demonstrated that 4-HPR concentration of 10(-6) M reduced the cellular motility by 29% in TSU-PR1 and 28% in PC-3 cells (p < 0.05). Spectrolyse PL indirect chromogenic assay revealed an increase in total activatable uPA activity (TSU-PR 1: 25%, PC-3: 32%, P < 0.05), while Spectrolyse UK direct assay demonstrated a mild, but a statistically significant reduction (PC-3: 5%, TSU-PR1: 9%, P < 0.05) in active uPA activity. Northern analysis and ELISA assays showed that 4-HPR at 10(-6) M enhances the expression of type 1 plasminogen activator inhibitor (PAI-1). Type IV collagenase western blot analysis and densitometry did not demonstrate suppression of the enzyme secretion, but in fact suggested increased translation of the enzyme when treated with 10(-6) M concentration of fenretinide. The results of this study demonstrate that 4-HPR inhibits in vitro cellular adhesion and motility of human prostate adenocarcinoma cell lines, TSU-PR1 and PC-3. Additionally, uPA and PAI-1 assay results suggest that 4-HPR may impair active uPA's proteolytic activity while upregulating the expression of total activatable uPA and PAI-1. The results of this study therefore support 4-HPR's role as a potential anti-invasive agent.
恶性侵袭的组成部分，即细胞黏附、运动能力和蛋白水解能力，为恶性肿瘤的药物干预提供了潜在靶点。在本研究中，进行了一系列实验，以检验N-(4-羟基苯基)视黄酸（4-HPR，芬维A胺）对已建立的前列腺癌细胞系TSU-PR 1和PC-3的细胞黏附、运动能力及蛋白水解活性的影响。放射性黏附研究表明，用10(-6) M的4-HPR处理TSU-PR 1和PC-3细胞后，细胞与基质胶提取物的黏附分别降低了32%和37%（p < 0.05）。放射性迁移试验还表明，10(-6) M的4-HPR浓度使TSU-PR1细胞的运动能力降低了29%，PC-3细胞降低了28%（p < 0.05）。Spectrolyse PL间接显色法显示可激活的尿激酶型纤溶酶原激活物（uPA）总活性增加（TSU-PR 1：25%，PC-3：32%，P < 0.05），而Spectrolyse UK直接检测法显示活性uPA活性有轻微但具有统计学意义的降低（PC-3：5%，TSU-PR1：9%，P < 0.05）。Northern分析和ELISA检测表明，10(-6) M的4-HPR可增强1型纤溶酶原激活物抑制剂（PAI-1）的表达。IV型胶原酶免疫印迹分析和光密度测定未显示该酶分泌受到抑制，实际上提示用10(-6) M浓度的芬维A胺处理后该酶的翻译增加。本研究结果表明，4-HPR可抑制人前列腺腺癌细胞系TSU-PR1和PC-3的体外细胞黏附和运动能力。此外，uPA和PAI-1检测结果提示，4-HPR可能损害活性uPA的蛋白水解活性，同时上调可激活的uPA和PAI-1的表达。因此，本研究结果支持4-HPR作为一种潜在抗侵袭剂的作用。
