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

Item Type:

Preprint

Title:

Creators Name:

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

Abstract:

Vitamin D deficiency is associated with an increased risk of prostate cancer (PCa) mortality and is hypothesized to contribute to PCa aggressiveness and disparities in African American populations. The prostate epithelium was recently shown to express megalin, an endocytic receptor that internalizes globulin-bound hormones, which suggests regulation of prostate hormone levels, in contrast to the free hormone hypothesis. Here, we demonstrated 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, indicating a negative feedback loop. In patent samples, the relationships between hormones support this feedback 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 PCa by the Gleason grade and in patients with future disease recurrence. 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 are known drivers of PCa. Thus, we revealed a mechanistic link between vitamin D and PCa disparities observed in African Americans.

Keywords:

Vitamin D, Androgen, Prostate Cancer, Disparities, Animals, Mice

Source:

bioRxiv

Publisher:

Cold Spring Harbor Laboratory Press

Article Number:

2021.11.09.467567v5

Date:

1 September 2022

Official Publication:

https://doi.org/10.1101/2021.11.09.467567

Related to:

URL	URL Type
https://edoc.mdc-berlin.de/23139/	Final version

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