Biblioteca Virtual en Salud

An androgen-independent (AI) prostate cancer cell line, derived recently from an LNCaP cell line maintained in androgen-poor conditions, has properties resembling a subgroup of advanced prostate cancers in that it has an overexpressed androgen receptor (AR), undetectable levels of p21 WAF and prostate-specific antigen, and is resistant to apoptosis. The loss of prostate-specific antigen expression but not the p21WAF is attributable to gene silencing by hypermethylation. The high AR and undetectable p21WAF of AI cells, and lower AR but highly expressed p21WAF of androgen-dependent perental LNCaP cells, suggest a possibility of a functional link between these two proteins. Therefore, we examined the impact the modulation of AR will have on the expression of p21WAF. Treatment of androgen-dependent cells with an androgen agonist, R1881, increased the AR protein level, wheras it silmultaneously reduced the endogenous p21WAF1-protein 8-fold and the activity of a transiently transfected p21-promoter-reporter 10-fold. The down-regulation of p21WAF1 promoter appeared to be ARE mediated, dependent on AR, and not cell-tyupe specific. Furthermore, a reduction of the AR level in AI cells by AR-antisense oligonucleotide increased the p21WAF1 promoter-reporter activity by 4-fold, confirming a functional link between these two proteins. A strong, direct induction of p21WAF1 expression achieved by treatment of AI cells with trichostatin A produced a partial reversion of the AI phenotype evidenced by increased sensitivity of these cells to paclitaxel-induced apoptosis. Moreover, a reduction of AR level by antisense treatment, which also increased p21WAF1 expression, partially restored the androgen dependen of AI cells for growth. The functional link between AR dosage and p21WAF1 expression suggests that therapeutic reduction of AR protein in advanced prostate cancers, with elevated AR levels may re-established their hormone dependence and improve therapeutic response to repeated hormonal ablation and/or induction of apoptosis