In vitro anti-invasive effects of N-(4-hydroxyphenyl)-retinamide on human prostatic adenocarcinoma.
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.
Kim
J H
JH
University of Chicago Hospital, Section of Urology, IL 60637, USA.
Tanabe
T
T
Chodak
G W
GW
Rukstalis
D B
DB
D000230:Adenocarcinoma / Q000188:drug therapy / Q000473:pathology*; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D017364:Collagenases / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D017313:Fenretinide / Q000494:pharmacology*; D006801:Humans; D008297:Male; D020780:Matrix Metalloproteinase 9; D009361:Neoplasm Invasiveness; D017395:Plasminogen Activator Inhibitor 1 / Q000032:analysis / Q000235:genetics; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000473:pathology*; D012333:RNA, Messenger / Q000032:analysis; D014407:Tumor Cells, Cultured; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism
D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D017313:Fenretinide; D014568:Urokinase-Type Plasminogen Activator; D017364:Collagenases; D020780:Matrix Metalloproteinase 9