Cancer-associated fibroblast-secreted glucosamine alters the androgen biosynthesis program in prostate cancer via HSD3B1 upregulation.
Oncology
Prostate cancer
Sex hormones
Journal
The Journal of clinical investigation
ISSN: 1558-8238
Titre abrégé: J Clin Invest
Pays: United States
ID NLM: 7802877
Informations de publication
Date de publication:
03 04 2023
03 04 2023
Historique:
received:
16
05
2022
accepted:
14
02
2023
medline:
4
4
2023
entrez:
3
4
2023
pubmed:
4
4
2023
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 37009898
pii: 161913
doi: 10.1172/JCI161913
pmc: PMC10065083
doi:
pii:
Substances chimiques
Androgens
0
Receptors, Androgen
0
Androgen Antagonists
0
Glucosamine
N08U5BOQ1K
Multienzyme Complexes
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NCI NIH HHS
ID : R50 CA251961
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA261995
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA236780
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA249279
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA172382
Pays : United States
Commentaires et corrections
Type : CommentIn
Type : CommentIn
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