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Supplement: Nutritional Genomics and Proteomics in Cancer Prevention

Pathways Mediating the Growth-Inhibitory Actions of Vitamin D in Prostate Cancer¹

Donna M. Peehl^*, Aruna V. Krishnan and David Feldman^,2

Departments of ^* Urology and Medicine, Stanford University School of Medicine, Stanford, CA 94305

² To whom correspondence should be addressed. E-mail: feldman{at}cmgm.stanford.edu.

Vitamin D is emerging as an important dietary factor that affects the incidence and progression of many malignancies including prostate cancer. The active form of vitamin D, 1,25-dihydroxycholecalciferol [1,25(OH)₂D₃], inhibits the growth and stimulates the differentiation of prostate cancer cells. We have studied primary cultures of normal and cancer-derived prostatic epithelial cells as well as established human prostate cancer cell lines to elucidate the molecular pathways of 1,25(OH)₂D₃ actions. These pathways are varied and appear to be cell specific. In LNCaP cells, 1,25(OH)₂D₃ mainly causes growth arrest through the induction of insulin-like growth factor binding protein-3 and also stimulates apoptosis to a much smaller extent. We have used cDNA-microarray analyses to identify additional genes that are regulated by 1,25(OH)₂D₃ and to raise novel therapeutic targets for use in the chemoprevention or treatment of prostate cancer. Less calcemic analogs of 1,25(OH)₂D₃ that have more antiproliferative activity are being developed that will be more useful clinically. In target cells, 1,25(OH)₂D₃ induces 24-hydroxylase, the enzyme that catalyzes its self inactivation. Cotreatment with 24-hydroxylase inhibitors enhances the antiproliferative activity of 1,25(OH)₂D₃. The combination of other anticancer agents such as retinoids with vitamin D offers another promising therapeutic approach. A small clinical trial has shown that 1,25(OH)₂D₃ can slow the rate of prostate-specific antigen increase in prostate cancer patients, which demonstrates proof of the concept that vitamin D or its analogs are clinically effective. Our research is directed at understanding the mechanisms of vitamin D action in prostate cells with the goal of developing chemoprevention and treatment strategies to improve prostate cancer therapy.

KEY WORDS: • 1,25-dihydroxVycholecalciferol • vitamin D analogs • vitamin D receptor • 24-hydroxylase • target genes

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