Untitled

Abstract

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.

Adipose Tissue-Derived Stem Cells Differentiate into Carcinoma-Associated Fibroblast-Like Cells under the Influence of Tumor-Derived Factors

“…TGF-β1 is considered to have a central role in inducing the myofibroblastic phenotype, because it is capable of up-regulating fibroblast α-SMA and collagen both in vitro and in vivo [28]. In many types of cancers, TGF-β1 is overexpressed by carcinoma cells [26], and it has been proposed previously that the expression of this cytokine by prostate carcinoma cells induces reactive stroma [30].…”

Characterization of Retinoic Acid Receptor-deficient Keratinocytes

“…Evidence for RAR-independent Mechanisms of Growth Inhibition by 4-HPR-4-HPR can inhibit growth and induce apoptosis in a number of model systems (44,64,65). Although this compound can act directly via the RARs, some of its effects may also be mediated by receptor-independent mechanisms (47,66).…”

Class IIb HDAC Inhibition Enhances the Inhibitory Effect of Am80, a Synthetic Retinoid, in Prostate Cancer

“…Retinoids have been reported to induce apoptosis in androgen-dependent and independent prostate cancer cells, [4][5][6][7] and the combination of retinoids with an organic arsenical or a histone deacetylase (HDAC) inhibitor induced apoptosis in several human and rodent prostate carcinoma cell lines in vitro and in vivo. 8,9) The reported molecular mechanisms of induction of apoptosis by retinoids in prostate cancer cells include down-regulation of Bcl-2 expression, 6,7,10,11) induction of insulin-like growth factor-binding protein-3 (IGFBP-3), 12) and accumulation of tissue transglutaminase in cells.…”