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.