Enhancement of Vitamin D Action in Prostate Cancer through Silencing of CYP24

This study focuses on the enzyme, CYP24 which hydroxylates vitamin D acting to catalyze the first step in the breakdown of Vitamin D, effectively limiting this growth inhibitory signaling pathway. We are testing the hypothesis that through the inhibition of CYP24 using an siRNA approach we can convert prostate cancer cells that are resistant to the antiproliferative actions of Vitamin D to cells that are growth inhibited at low concentrations of Vitamin D. Inhibition of 1,25OH2D3 CYP24 mediated metabolism to potentiate Vitamin D actions in prostate cancer shows great potential for both a chemopreventative approach and the treatment of advanced hormone refractory cancer in patients. We have tested CYP24 siRNA constructs, ketoconazole and silencer control siRNA on three cell lines LNCaP, PC3 and DU145 and evaluated CYP24 protein expression, mRNA expression, and growth inhibition. We are in the process of developing the stable transfected cell lines and optimal approach to enhance Vitamin D action in resistant cells.