ArticleCancer research2026
Androgen Receptor Drives Polyamine Synthesis, Creating a Vulnerability for Prostate Cancer.
Article in Cancer research, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed.
- A biomarker-driven approach to targeting polyamine depletion in triple negative breast cancer.Biomarker research · 2026Article
- SAT1 promotes prostate cancer progression and decreases enzalutamide sensitivity by enhancing spermine catabolism.Human cell · 2026Article
- Dysregulation of the urea cycle - potential targets for treatment and diagnosis in prostate cancer.Expert reviews in molecular medicine · 2026Review
- Article
- Emerging biomarkers in prostate cancer diagnosis and treatment: Insights into genetic, RNA and metabolic markers (Review).International journal of oncology · 2026Review
- Polyamine metabolism in prostate cancer.Current opinion in oncology · 2025Review
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27 authors.
Funding
Abstract
Supraphysiologic androgen (SPA) treatment can paradoxically restrict the growth of castration-resistant prostate cancer (CRPC) with high androgen receptor (AR) activity, which is the basis for the use of bipolar androgen therapy (BAT) for patients with this disease. Although androgens are widely appreciated for enhancing anabolic metabolism, how SPA-mediated metabolic changes alter prostate cancer progression and therapy response is unknown. In this study, we report that SPA markedly increased intracellular and secreted polyamines in prostate cancer models. AR binding at enhancer sites upstream of the ornithine decarboxylase 1 (ODC1) promoter increased the abundance of ODC, a rate-limiting enzyme of polyamine synthesis, and de novo synthesis of polyamines from arginine. SPA-stimulated polyamines enhanced prostate cancer fitness, as dCas9-KRAB-mediated inhibition of AR regulation of ODC1 or direct ODC inhibition by difluoromethylornithine (DFMO) increased the efficacy of SPA. Mechanistically, AR activation combined with the loss of negative feedback by polyamines increased the activity of S-adenosylmethionine decarboxylase 1, leading to the depletion of its substrate, S-adenosylmethionine, and global protein methylation. These data provided the rationale for a clinical trial testing the safety and efficacy of BAT in combination with DFMO for patients with metastatic CRPC. Pharmacodynamic studies of this therapeutic combination in the first five patients in the trial indicated that this approach effectively depleted polyamines in plasma. Thus, the AR potently stimulates polyamine synthesis, which constitutes a vulnerability in prostate cancer treated with SPA that can be targeted therapeutically. SIGNIFICANCE: Increased polyamine synthesis is a prominent metabolic change induced by the androgen receptor that drives tumor progression and confers a targetable vulnerability in advanced prostate cancer. See related commentary by Alizadeh-Ghodsi and Goldstein, p. 1095.
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