Cancer-associated fibroblast-secreted glucosamine alters the androgen biosynthesis program in prostate cancer via HSD3B1 upregulation
Di Cui, … , Belinda Willard, Nima Sharifi
Di Cui, … , Belinda Willard, Nima Sharifi
Published April 3, 2023
Citation Information: J Clin Invest. 2023;133(7):e161913. https://doi.org/10.1172/JCI161913.
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Research Article Oncology

Cancer-associated fibroblast-secreted glucosamine alters the androgen biosynthesis program in prostate cancer via HSD3B1 upregulation

Abstract

After androgen deprivation, prostate cancer frequently becomes castration resistant (CRPC), with intratumoral androgen production from extragonadal precursors that activate the androgen receptor pathway. 3β-Hydroxysteroid dehydrogenase-1 (3βHSD1) is the rate-limiting enzyme for extragonadal androgen synthesis, which together lead to CRPC. Here, we show that cancer-associated fibroblasts (CAFs) increased epithelial 3βHSD1 expression, induced androgen synthesis, activated the androgen receptor, and induced CRPC. Unbiased metabolomics revealed that CAF-secreted glucosamine specifically induced 3βHSD1. CAFs induced higher GlcNAcylation in cancer cells and elevated expression of the transcription factor Elk1, which induced higher 3βHSD1 expression and activity. Elk1 genetic ablation in cancer epithelial cells suppressed CAF-induced androgen biosynthesis in vivo. In patient samples, multiplex fluorescent imaging showed that tumor cells expressed more 3βHSD1 and Elk1 in CAF-enriched areas compared with CAF-deficient areas. Our findings suggest that CAF-secreted glucosamine increases GlcNAcylation in prostate cancer cells, promoting Elk1-induced HSD3B1 transcription, which upregulates de novo intratumoral androgen synthesis to overcome castration.

Authors

Di Cui, Jianneng Li, Ziqi Zhu, Michael Berk, Aimalie Hardaway, Jeffrey McManus, Yoon-Mi Chung, Mohammad Alyamani, Shelley Valle, Ritika Tiwari, Bangmin Han, Maryam Goudarzi, Belinda Willard, Nima Sharifi

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Figure 5

Elk1 induced 3βHSD1 expression and DHEA metabolism in vivo.

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Elk1 induced 3βHSD1 expression and DHEA metabolism in vivo. (A) Cell via...
(A) Cell viability of sgControl and ELK1-KO LNCaP cells treated with DMSO (control) or 10 nM DHEA for 48 hours. (B) Xenograft tumor growth of orchiectomized mice subcutaneously injected with control or ELK1-KO C42 cells in the absence or presence of CAFs. A 2-tailed paired t test was performed between control and ELK1-KO tumors coinjected with CAFs at day 21. (C) A log-rank test was used to compare progression-free survival between control and ELK1-KO and C4-2 cells grown with CAFs. (D) Mass spectrometry analysis of intratumoral and serum DHEA, AD, and testosterone (T) in control or ELK1-KO C42 cells. (E) Representative multiplexed fluorescence image of a patient with prostate cancer (Gleason 4+4). 3βHSD1, orange; Elk1, green; CAF, α-SMA, purple), and DAPI, blue. Scale bar: 50 μm. Pearson correlation analysis of gene expression in tissues from patients with primary prostate cancer (3βHSD1 and CAF [α-SMA], n = 22; 3βHSD1 and Elk1, n = 14). (F) Pearson correlation analysis of HSD3B1 and FAP mRNA (CAF) in human CRPC metastases (GSE77930). Unless otherwise noted, data are shown as mean ± SEM. Significance was calculated using a 2-tailed t test or 1-way ANOVA. *P < 0.05, **P < 0.01.