Down-regulation of Skp2 is correlated with p27-associated cell cycle arrest induced by phenylacetate in human prostate cancer cells.

We have demonstrated that phenylacetate (PA)induced cell cycle arrest in human prostate cancer is mediated by increase of p27. In this study, we further investigated the mechanism of PA-induced p27 expression in prostate cancer cells (LNCaP, androgen-independent LNCaP [AIDL] and PC-3). A striking decrease in Skp2 mRNA and protein expression and reciprocal increase in p27 protein level were observed in three PA-treated prostate cancer cells. Interestingly, reduction of phospho-Akt and up-regulation of p27 mRNA levels were observed only in PC-3 cells. No significant differences were found in phospho-Akt and p27 mRNA levels in LNCaP and AIDL. In vitro ubiquitination assay showed a decreased p27 ubquitination in PA-treated prostate cancer cells. Our results suggest that PA attenuated Skp2 expression, thereby inhibiting ubiquitination and promoting p27 accumulation in all three prostate cancer cell lines. Therapeutic strategies designed to reduce Skp2 may clinically play an important role in the treatment of both androgen-sensitive and hormone-refractory prostate cancer.