PT - JOURNAL ARTICLE AU - Jason Garcia AU - Kirsten D. Krieger AU - Candice Loitz AU - Lillian Perez AU - Zachary A. Richards AU - Yves Helou AU - Steve Kregel AU - Sasha Celada AU - Clementina A. Mesaros AU - Peter H. Gann AU - Thomas E. Willnow AU - Donald Vander Griend AU - Rick Kittles AU - Gail S. Prins AU - Trevor Penning AU - Larisa Nonn TI - Prostate megalin is regulated by serum hormone levels and imports globulin-bound testosterone AID - 10.1101/2021.11.09.467567 DP - 2022 Jan 01 TA - bioRxiv PG - 2021.11.09.467567 4099 - http://biorxiv.org/content/early/2022/02/27/2021.11.09.467567.short 4100 - http://biorxiv.org/content/early/2022/02/27/2021.11.09.467567.full AB - 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. We previously reported 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 show prostatic 5α-dihydrotestosterone (DHT) levels are higher in African American men and inversely correlate with serum 25-hydroxyvitamin D (25D) status. We further 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 was suppressed by 25D and DHT in cell lines, patient-derived prostate epithelial cells, and prostate tissue explants, supporting a negative feedback loop. 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.Competing Interest StatementThe authors have declared no competing interest.