A long latent period of 20 to 30 years may be involved in the multistep process of
carcinogenesis represented by
prostatic intraepithelial neoplasia (PIN) in the prostate. It is, therefore, possible that progression to a malignant state could be blocked or reversed during this time.
Retinoids not only have the ability to block steps in the process of
carcinogenesis but they may also modulate or reverse some malignant characteristics of
cancer cells. 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. These malignant characteristics include abnormal cell proliferation, intermediate filament expression, motility, invasion, and cell survival. Results show that 1 microM and 10 microM
4-HPR caused 31% and 96% inhibition of growth, while all-trains
retinoic acid (ATRA) produced similar effects
at 10 and 100 microM, making
4-HPR ten times more effective than ATRA. While DU-145 cells show strong immunostaining for
vimentin, treatment with 1 microM
4-HPR for eight days caused a marked decrease in
vimentin staining. This was accompanied by a change from an elongated to an epithelial cell morphology. Densitometric analysis of Western blots for
vimentin showed a 53% decrease in
vimentin expression in 1 microM
4-HPR treated cells. Concomitant with the decrease in
vimentin expression, cell motility and invasive ability also decreased by 32% and 52%, respectively. Growth inhibition was accompanied by DNA fragmentation and apoptosis. Exposure of cells to 1 microM
4-HPR caused a marked upregulation of nuclear
retinoid receptors RARalpha and a detectable expression of RARgamma. These results suggest that inhibition of growth and
vimentin 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 intermediate marker for early detection of
prostate cancer in biopsy specimens and that
4-HPR may be effective in blocking several steps in prostate
carcinogenesis as well as the progression of PIN to invasive
carcinoma.