Dataset Information

Androgenic Effects of 11-oxyandrogens in Castration-Resistant Prostate Cancer

ABSTRACT: Investigations of CRPC cell models demonstrate that 11-ketotestesterone (11KT) and 11-hydroxytestosterone (11OHT) drive robust AR-mediated proliferative responses and significantly modulate gene and protein expression profiles, paralleling canonical androgens. They also exhibit unique transcriptional and post-transcriptional effects that include potential AR-independent pathways. Furthermore, the AR antagonist enzalutamide effectively inhibits their androgenic actions, suggesting they are primarily AR-mediated.

INSTRUMENT(S): timsTOF Pro

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Chantal Guillemette

PROVIDER: MSV000097860 | MassIVE | Tue May 13 13:28:00 BST 2025

SECONDARY ACCESSION(S): PXD063893

REPOSITORIES: MassIVE

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Androgenic effects of 11-oxyandrogens in castration-resistant prostate cancer.

Lapointe-Belleau Ariane A Rouleau Michèle M Villeneuve Lyne L Descarreaux Joseph J Caron Patrick P Beaudoin Caroline C Uchil Ashwini A Simonyan David D Dahmani Cylia C Joly-Beauparlant Charles C Gélinas Vincent V Droit Arnaud A Marcoux Nicolas N Castonguay Vincent V Lacombe Louis L Lévesque Éric É Guillemette Chantal C

BMC cancer 20251119 1

BACKGROUND: Adrenal-derived 11-oxygenated androgens (11-oxyandrogens) emerged as potential key contributors to prostate cancer (PCa) progression by activating the androgen receptor (AR). This study investigates their clinical and mechanistic role in metastatic castration-resistant prostate cancer (mCRPC) patients initiating AR pathway inhibitors (ARPI). METHODS: In a pilot study of 35 mCRPC patients initiating ARPI, serum steroids were quantified via mass spectrometry and correlated with surviva ...[more]

PMID: 41257618

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Project description:Background: High-grade serous ovarian cancer (HGSOC) is the most lethal gynaecological malignancy, exhibiting marked heterogeneity that complicates treatment. The implications of intratumoral androgen metabolism and signalling, particularly involving 11-oxygenated androgens, in HGSOC remains poorly understood. Methods: We analysed expression of key androgen-metabolizing enzymes and androgen receptor (AR) in relation to tumor site, chemotherapy response, and survival using two public HGSOC cohorts. Quantitative gene expression and steroid metabolism assays upon incubation with classic and 11-oxyandrogen precursors were performed in six HGSOC cell lines and one normal ovarian epithelial line. Untargeted transcriptomic and metabolomic profiling were performed to assess cellular responses to potent classic and 11-oxygenated androgens in the AR-positive OVSAHO cell line. Results: Differential expression of steroid-metabolizing enzymes and AR were observed between primary and metastatic tumors and chemo-sensitive and chemo-resistant tumors. Higher intra-tumoral expression of HSD11B2, HSD17B2, and AR correlated with improved survival, whereas elevated PAPSS1/2 and HSD17B4 predicted poorer outcomes. In vitro, classic androgen precursors showed limited conversion to bioactive androgens and did not generate 11-oxyandrogens. In contrast, 11-oxyandrogen precursors were efficiently converted to the potent AR agonist 11KT in chemo-sensitive HGSOC cell lines, but not in chemo-refractory or control lines. Potent classic and 11-oxyandrogens induced stress-adaptive and proliferative transcriptional responses and reduced intracellular amino acid content. These changes were associated with a trend toward reduced cell proliferation. Conclusions: Our findings offer mechanistic insight into local androgen and 11-oxyandrogen metabolism and signalling in HGSOC and reveal steroid-induced cellular vulnerabilities that may synergize with chemotherapy or molecularly targeted therapies. These results further support the therapeutic potential of modulating steroid pathways in HGSOC.