The Cell Cycle Inhibitor p27KIP1: A Key of G1 Arrest by Androgen Ablation and by Vitamin D3 Analog

Our previous research in LNCaP and in vivo in prostate cancers suggested that the cell cycle inhibitor, p27, is an important effector of growth arrest in the prostate. In the work of the last 2 years, we have shown that the cell cycle regulator, p27, mediates growth arrest by the vitamin D3 analog, EB 1089. Work during final year of the grant period has addressed how processes regulating p27 are altered during prostate cancer progression. Effects of androgens and vDR activation by EB 1089 on p27 function were assayed. We demonstrated that physiologic concentrations of DHT and EB 1089 have synergistic effects to upregulate p27 and inhibit growth of prostate cancer cells. This work has led us to assay the effects of a combination of low dose DHT and EB 1089 in pre-clinical trials using LNCaP xenografts in immunodeficient mice. Our preliminary data analysis of these in vivo studies in mouse models suggest that DHT and EB 1089 causes synergistic inhibition of prostate cancer growth and can prevent tumor formation in nude mouse models in this in vivo mouse model. Data from these studies would support the inception of clinical trials of the combination of low dose DHT and EB 1089 in prostate cancer patients. Unraveling the pathways whereby these steroid hormones influence the cell cycle has defines p27 as a novel target for anti-prostate cancer drugs. Moreover, our studies of p27 protein expression before and after NHT may provide a new marker to identify hormone resistant primary prostate cancers and stimulate development of novel treatment strategies.