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

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Item Type:

Article

Title:

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

Creators Name:

Garcia, J. and Krieger, K.D. and Loitz, C. and Perez, L.M. and Richards, Z.A. and Helou, Y. and Kregel, S. and Celada, S. and Mesaros, C.A. and Bosland, M. and Gann, P.H. and Willnow, T.E. and Vander Griend, D. and Kittles, R. and Prins, G.S. and Penning, T. and Nonn, L.

Abstract:

Vitamin D deficiency is associated with an increased risk of prostate cancer mortality and is hypothesized to contribute to prostate cancer aggressiveness and disparities in African American populations. The prostate epithelium was recently shown to express megalin, an endocytic receptor that internalizes circulating globulin-bound hormones, which suggests regulation of intracellular prostate hormone levels. This contrasts with passive diffusion of hormones that is posited by the free hormone hypothesis. Here, we demonstrate that megalin imports testosterone bound to sex hormone-binding globulin into prostate cells. Prostatic loss of Lrp2 (megalin) in a mouse model resulted in reduced prostate testosterone and dihydrotestosterone (DHT) levels. Megalin expression was regulated and suppressed by 25-hydroxyvitamin D (25D) in cell lines, patient-derived prostate epithelial cells, and prostate tissue explants. In patients, the relationships between hormones support this regulatory mechanism, as prostatic DHT levels are higher in African American men and are inversely correlated with serum 25D status. Megalin levels are reduced in localized prostate cancer by Gleason grade. Our findings suggest that the free hormone hypothesis should be revisited for testosterone and highlight the impact of vitamin D deficiency on prostate androgen levels, which is a known driver of prostate cancer. Thus, we revealed a mechanistic link between vitamin D and prostate cancer disparities observed in African Americans.

Keywords:

Androgens, Black or African American, Calcifediol, Low Density Lipoprotein Receptor-Related Protein-2, Prostate, Prostatic Neoplasms, Testosterone, Vitamin D, Vitamin D Deficiency, Animals, Mice

Source:

Cancer Research Communications

ISSN:

2767-9764

Publisher:

American Association for Cancer Research

Volume:

Number:

Page Range:

371–382

Date:

3 March 2023