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

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Annual rept. 4 Jan 1999-3 Jan 2000

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Our data in LNCaP and in vivo in prostate cancers suggest that the cell cycle inhibitor, p27, is an important effector of growth arrest in the prostate. In the work of the last year, we identified that the cell cycle regulator, p27, mediates growth arrest by the vitamin D3 analog, EB1089. Work during the remainder of the grant period will address how processes regulating p27 are altered during prostate cancer progression. Effects of VDR activation and androgens on p27 function will be assayed. Experiments will clarify how phosphorylation affects p27 stability and its association with novel protein regulators and target cdks. We demonstrated the synergistic effect of physiologic concentrations of DHT and EB1089 to upregulate p27 and inhibit growth of prostate cancer cells. This work has led to our proposal to assay the effects of a combination of low dose DHT and EB1089 in pre-clinical trials using LNCaP xenografts in immunodeficient mice. If the synergistic effects of DHT and EB1089 to inhibit growth of prostate cancers or prevent tumor formation in nude mouse models are confirmed, these studies could lead to clinical trials in prostate cancer patients. Unraveling the pathways whereby these steroid hormones influence the cell cycle may define novel targets 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.

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  • Anatomy and Physiology
  • Medicine and Medical Research

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