Abstract A089: Challenging the free hormone hypothesis for vitamin D in the prostate has implications for the prostate cancer disparity in African American men

Abstract

Abstract African American (AA) men are disproportionately at risk for both prostate cancer (PCa) and vitamin D (vitD) deficiency compared to European American (EA) men. Based on the numerous chemopreventative properties of vitD and its status with PCa aggressiveness and mortality, vitD deficiency has been hypothesized as a biologic contributor to the PCa disparity in AA men. We recently reported that despite having deficient levels of vitD in the serum, AAs have higher levels of vitD in their prostate tissue compared to EAs. This suggests a mechanism of active vitD transport across the membrane and challenges the longstanding free hormone hypothesis, which asserts that the activity of a hormone is due to the bioavailable fraction and its passive diffusion across the membrane. The majority of VitD circulates bound to D binding protein (DBP) and is sequestered in the serum, rendering it unavailable for passive diffusion. A mechanism of active DBP-vitD endocytosis has been well characterized in the kidney by the extracellular receptor megalin. We hypothesized that megalin is functional in prostate epithelium and facilitates adequate prostatic vitD levels in AAs with vitD deficiency. Here, we report megalin protein expression in prostate tissue, LNCaP, and primary human prostate cells. Megalin function was further assessed in primary human-derived organoids treated with 25D in the presence or absence of DBP. Surprisingly, vitD import and metabolism occurred faster in +DBP conditions and suggests that DBP-vitD active transport is more efficient than passive diffusion of vitD alone. VDR activation was diminished in a dose-responsive manner by addition of a megalin antagonist. Additionally, megalin protein levels in PCa were significantly lower compared to benign (p<0.05) on a tissue microarray quantified by immunofluorescent staining. In summary, our data support a model of megalin-mediated active transport for vitD in the prostate and demonstrate ancestry-related and PCa differences in megalin regulation. These findings challenge the free hormone hypothesis and postulate that vitD deficiency is more complex than previously thought. Citation Format: Zachary Richards, Larisa Nonn. Challenging the free hormone hypothesis for vitamin D in the prostate has implications for the prostate cancer disparity in African American men [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A089.