Elevated prostate androgens in African American men mediated by megalin import of testosterone and 25-hydroxyvitamin D status

Vitamin D deficiency associates with an increased risk of prostate cancer (PCa) mortality and is hypothesized to contribute to PCa aggressiveness and disparities in African Americans. There is a relationship between African-ancestry, circulating and intraprostatic vitamin D metabolites and prostatic expression of megalin, an endocytic receptor that internalizes globulin-bound hormones. Here, we demonstrate that megalin imports sex hormone-binding globulin-bound testosterone in prostate cells and prostatic loss of Lrp2 (megalin) results in reduced prostate androgen levels. Megalin expression is suppressed by 25-hydroxyvitamin D (25D) in cell lines, patient-derived prostate epithelial cells, and prostate tissue explants, indicating a negative feedback loop. The relationships between hormones in patients support this feedback as prostatic DHT levels are higher in African American men and inversely correlate with serum 25D status. Megalin levels are reduced in localized PCa by Gleason Grade and in patients with future disease recurrence. Our findings highlight the impact of vitamin D deficiency on prostate androgen levels, which are known drivers of PCa, and reveal a potential mechanistic link between vitamin D and the PCa disparities observed in African Americans.