N-(4-hydroxyphenyl)retinamide (4-HPR) decreases neoplastic properties of human prostate cells: an agent for prevention.
The development of prostate cancer through a multistep process of carcinogenesis may have a long latent period of 20-30 years. It is possible that progression to a malignant state could be blocked or reversed during this time. This study focuses on the ability of the synthetic retinoid, N-(4-hydroxyphenyl)-retinamide (4-HPR), to reverse changes associated with malignant transformation and tumor progression, towards a normal phenotype. To examine the responsiveness of cells at different steps of prostate carcinogenesis, three immortalized, but non-tumorigenic (RWPE-1, WPE1-7 and WPE1-10), and one human prostate carcinoma cell line (DU-145), were used. The effects of 4-HPR on cell proliferation, expression of intermediate filament proteins cytokeratin 18 and vimentin, and tumor suppressor proteins p53 and pRb were examined by immunostaining and compared. Results show that 4-HPR caused inhibition of growth in all cell lines in a dose-dependent manner. 4-HPR induced an increase in staining for cytokeratin 18, a marker of differentiation for prostate epithelial cells. While all cell lines showed strong immunostaining for vimentin, treatment with 4-HPR for 8 days caused a marked decrease in staining for vimentin in all cell lines. In an in vitro assay, 4-HPR also caused inhibition of invasion by DU-145 cells in a dose-dependent manner. Furthermore, 4-HPR treatment was effective in significantly decreasing the abnormal nuclear staining for the tumor suppressor proteins p53 and pRb. Because 4-HPR decreased invasion-associated vimentin expression, inhibited invasion, and normalized p53 and pRb immunostaining, we propose that 4-HPR may be an effective agent for secondary and tertiary prevention, i.e. promotion and progression stages, respectively, of prostate cancer.
Sharp
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RM
Department of Zoology, S-350 Plant Biology Building, Michigan State University, East Lansing, MI 48824-1312, USA.
Bello-DeOcampo
D
D
Quader
S T
ST
Webber
M M
MM
D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D002452:Cell Count; D002455:Cell Division / Q000187:drug effects; D002461:Cell Line, Transformed / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D017313:Fenretinide / Q000494:pharmacology*; D006801:Humans; D007124:Immunoenzyme Techniques; D007633:Keratins / Q000378:metabolism; D008297:Male; D009361:Neoplasm Invasiveness / Q000517:prevention & control; D010641:Phenotype; D011467:Prostate / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D011471:Prostatic Neoplasms; D016160:Retinoblastoma Protein / Q000378:metabolism; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014746:Vimentin / Q000378:metabolism
D016588:Anticarcinogenic Agents; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; D014746:Vimentin; D017313:Fenretinide; D007633:Keratins