Modulation of the malignant phenotype of human prostate cancer cells by N-(4-hydroxyphenyl)retinamide (4-HPR)

A long latent period of 20 to 30 years may be involved in the multistep pro cess of carcinogenesis represented by prostatic intraepithelial neoplasia ( PIN) in the prostate. It is, therefore, possible that progression to a mali gnant state could be blocked or reversed during this time. Retinoids not on ly have the ability to block steps in the process of carcinogenesis but the y may also modulate or reverse some malignant characteristics of cancer cel ls. This study focuses on the ability of N-(4-hydroxyphenyl)-retinamide (4- HPR), a synthetic retinoid, to reverse malignant characteristics towards a normal phenotype, using the human prostate carcinoma cell line DU-145. Thes e malignant characteristics include abnormal cell proliferation, intermedia te filament expression, motility, invasion, and cell survival. Results show that 1 mu M and 10 mu M 4-HPR caused 31% and 96% inhibition of growth, whi le all-trans retinoic acid (ATRA) produced similar effects at 10 and 100 mu M, making 4-HPR ten times more effective than ATRA. While DU-145 cells sho w strong immunostaining for vimentin, treatment with 1 mu M 4-HPR for eight days caused a marked decrease in vimentin staining. This was accompanied b y a change from an elongated to an epithelial cell morphology. Densitometri c analysis of Western blots for vimentin showed a 53% decrease in vimentin expression in 1 mu M 4-HPR treated cells. Concomitant with the decrease in vimentin expression, cell motility and invasive ability also decreased by 3 2% and 52%, respectively. Growth inhibition was accompanied by DNA fragment ation and apoptosis. Exposure of cells to 1 mu M 4-HPR caused a marked upre gulation of nuclear retinoid receptors RAR alpha and a detectable expressio n of RAR gamma. These results suggest that inhibition of growth and vimenti n expression, and induction of apoptosis by 4-HPR in prostate cancer cells may occur via a receptor-mediated mechanism involving transrepression of AP -1 by retinoid receptors. We propose that vimentin may serve as a useful in termediate marker for early detection of prostate cancer in biopsy specimen s and that 4-HPR may be effective in blocking several steps in prostate car cinogenesis as well as the progression of PIN to invasive carcinoma.