Androgen receptor regulation of G1 cyclin and cyclin-dependent kinase function in the CWR22 human prostate cancer xenograft

Human prostate cancer is initially dependent on androgens for growth, and a ndrogen-dependent cells undergo apoptosis after castration. However, a subs et of androgen-responsive cells survives and eventually proliferates in the absence of testicular androgen. The high levels of androgen receptor in bo th androgen-dependent and recurrent tumors led us to investigate androgen r egulation of cell cycle proteins in human prostate cancer using the CWR22 x enograft, Cellular proliferation decreased dramatically in CWR22 tumors aft er castration. Testosterone propionate (TP) treat ment of castrated mice re stored cellular proliferation after 24-48 hours. Growth of CWR22 tumors in the absence of testicular androgen recurred several months after castration . CDK1 and CDK2, and cyclin A and cyclin B1 messenger RNAs were decreased 6 days after castration, increased 6-12 hours after TP treatment, and were e xpressed at high levels in recurrent CWR22 tumors. Coimmunoprecipitated cyc lin B1/CDK1 and cyclin D1/CDK4 protein complexes decreased after castration and increased after TP treatment of castrated mice. In addition, CDK1 and CDK2 kinase activities were upregulated by androgen in parallel with hyperp hosphorylation of retinoblastoma (Rb) protein. Despite the absence of testi cular androgen in recurrent CWR22, the levels of these androgen-regulated c yclin/CDK protein complexes and hyperphosphorylation of Rb were equal to or greater than in tumors from intact mice. The results indicate that androge n receptor regulates cellular proliferation by control of CDK and cyclins a t the transcriptional level and by post-translational modifications that in fluence cell cycle protein activity.