Journal Article

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

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

2023

Overview

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.

• Publisher: American Society for Clinical Investigation
• Subject: Androgen Antagonists / Androgen receptors / Androgen suppression therapy / Androgens / Androgens - metabolism / Biomedical research / Biosynthesis / Cancer-Associated Fibroblasts - metabolism / Care and treatment / Castration / Cell Line, Tumor / Complications and side effects / Cytokines / Dehydrogenases / Development and progression / Enzymes / Epithelial cells / Fibroblasts / Genetic aspects / Genetic transcription / Glucosamine / Growth factors / Health aspects / Humans / Male / Metabolism / Metabolites / Metabolomics / Metastasis / Multienzyme Complexes - genetics / Oncology / Patient outcomes / Physiological aspects / Prostate cancer / Prostatic Neoplasms - pathology / Prostatic Neoplasms, Castration-Resistant - genetics / Proteins / Receptors, Androgen - genetics / Receptors, Androgen - metabolism / Transcription factors / Tumor cells / Type 2 diabetes / Up-Regulation