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.
<p>S1. Accompanies Figure 1 and 2.</p><p>S2. Accompanies Figure 2. No differences in bitransgenic mouse prostate histology, weights and fertility.</p><p>S3. Relates to Figure 3. Vitamin D receptor and androgen receptor response elements in LRP2 promoter.</p><p>S4. Relates to Figure 3. Prostate slices express hormone response components and respond to 25D and T.</p><p>S5. Relates to Figure 4. Androgen levels by Gleason and Age.</p><p>S6. Relates to Figure 6. Expression of LRP2 by age and BCR in DFKZ and TCGA cohorts.</p><p>Table S1. Cell and tissue characteristics</p><p>Table S2. Primer sequences</p>
<div><p>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 <i>Lrp2</i> (megalin) in a mouse model resulted in reduced prostate testosterone and dihydrotestosterone 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.</p>Significance:<p>These findings link vitamin D deficiency and the megalin protein to increased levels of prostate androgens, which may underpin the disparity in lethal prostate cancer in African America men.</p></div>
<p>S1. Accompanies Figure 1 and 2.</p><p>S2. Accompanies Figure 2. No differences in bitransgenic mouse prostate histology, weights and fertility.</p><p>S3. Relates to Figure 3. Vitamin D receptor and androgen receptor response elements in LRP2 promoter.</p><p>S4. Relates to Figure 3. Prostate slices express hormone response components and respond to 25D and T.</p><p>S5. Relates to Figure 4. Androgen levels by Gleason and Age.</p><p>S6. Relates to Figure 6. Expression of LRP2 by age and BCR in DFKZ and TCGA cohorts.</p><p>Table S1. Cell and tissue characteristics</p><p>Table S2. Primer sequences</p>
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.
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