Role of Vitamin D Stimulation of Mullerian Inhibiting Substance (MIS) in Prostate Cancer Therapy

摘要

This grant investigates the potential use of calcitriol regulation of mullerian inhibitory substance (MIS) expression as an incremental therapy for prostate cancer. We have established that calcitriol (1,25-dihydroxyvitamin D3) directly stimulates MIS expression by binding to the vitamin D receptor (VDR) and directing the hormone-receptor complex to bind to a vitamin D regulatory element (VDRE) in the MIS promoter. We have attempted to demonstrate that combination of calcitriol and MIS achieve increased potency to inhibit prostate cancer cell growth compared to either drug alone. However, this has not yet been definitively accomplished although new data are included in this revised report. We further demonstrated the interaction of calcitriol-VDR with other transcription factors, SF-1, SOX-9 and GATA-4, to act together to synergistically increase MIS expression in prostate cancer cells. We believe that some of calcitriol's action to inhibit prostate cancer cell growth are due to stimulation of MIS and this work plans to substantiate this hypothesis and lay the ground work to translate this information to clinical trials in men with prostate cancer. The major focus of the work completed was to document the VDRE in the MIS promoter. This has now been completed and the manuscript published. Preliminary data showing further effects of MIS with and without calcitriol are now included in this report and the findings are confusing.