Prostate cancer (PCa) is the most frequently diagnosed cancer in African American men. African American men died of PCa in a 2.39-fold higher rate as compared with Caucasian counterparts. For patients with the metastasis PCa, androgen-deprivation chemotherapy is commonly applied and results in an initial regression of PCa. However, the relapses of this malignance were reported in many cases, and eventually PCa patients still died of recurrent growth of Castration Resistant Prostate Cancer (CRPC). Molecular mechanisms contributing to CRPC remain poorly understood. The purpose of this research is to define anticancer effects of Skp2 inactivation on the recurrence of CRPC using mouse models. In this experiment, Pten/p53 conditional double and Pten/p53/Skp2 conditional triple knockout mice were generated, and prostate tumorigenesis was evaluated and compared under the condition of castration and non-castration in mice. Here we report for the first time that Skp2 inactivation significantly inhibits the recurrence of CRPC in mice using Pten/p53 conditional mouse models. Loss of Skp2 significantly suppresses both the initiation and progression of prostate tumorigenesis in Pten/p53 mutant mice at 3 months of age and 6 months of age, respectively. Prostate tumors of Pten/p53/Skp2 triple mutant mice are significantly smaller as compared to that of age-matched Pten/p53 double mutant mice. Pathological analysis revealed that triple mutant mice develop less aggressive phenotype of prostate cancer than double mutant mice. Pten/p53 mice responded to surgery castration by decreasing the size of prostate tumors initially, but the recurrent growth of prostate cancer resulted in the death of all mice at 6 months of age. Most importantly, loss of Skp2 remarkably inhibits the recurrent growth of CRPC in Pten/p53 mutant mice. Three months post castration, prostate tumor weights of Pten/p53/Skp2 mutant mice were significantly decreased as compared to that of age-matched Pten/p53 mutant mice. Suppression on the recurrent growth of CRPC by Skp2 inactivation is contributed by induction of G2 cell cycle arrest and cellular senescence. Our findings suggest that drugs targeting on Skp2 function may be a novel and effective chemotherapy option to control CRPC in patients.
Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):B74.