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 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 that megalin imports sex hormone-binding globulin (SHBG)-bound testosterone, potentially regulating intraprostatic hormone levels. Vitamin D levels regulated megalin expression in cell lines, patient-derived prostate epithelial cells, and prostate tissue explants, and mice with prostatic knockout of Lrp2 (megalin) showed reduced prostatic testosterone. Notably, prostatic 5α-dihydrotestosterone levels were higher in African American men and correlated inversely with serum vitamin D status, while megalin protein levels were reduced in PCa tissue. Our findings highlight the negative impact of vitamin D deficiency on PCa and the potential link to PCa disparities observed in African Americans.
Competing Interest Statement
The authors have declared no competing interest.