Regulation of prostate androgens by megalin and 25-hydroxyvitamin D status: Mechanism for high prostate androgen in African American men

Abstract

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 membrane receptor that internalizes globulin-bound hormones. Here, we show prostatic 5α-dihydrotestosterone levels were higher in African American men and correlated inversely with serum vitamin D status. We further demonstrate that megalin imports sex hormone-binding globulin (SHBG)-bound testosterone and regulates intraprostatic hormone levels in a prostatic knockout of Lrp2 (megalin). Vitamin D and androgen regulated megalin expression in cell lines, patient-derived prostate epithelial cells, and prostate tissue explants. Megalin levels oscillated during PCa progression, further supporting a role in androgen import. Our findings highlight the negative impact of vitamin D deficiency on PCa and a link to PCa disparities observed in African Americans.