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Androgen receptor drives polyamine synthesis creating a vulnerability for prostate cancer

ABSTRACT: The androgen receptor (AR) enacts metabolic effects of the anabolic steroid testosterone, but how AR-directed metabolic changes affect prostate cancer progression is not well understood. Here, we show that the AR increases de novo polyamine synthesis by direct transcriptional regulation of ornithine decarboxylase (ODC) expression across cell types, including prostate cancer cells. Likewise, androgen treatment of prostate cancer models increased intracellular and secreted polyamines, a process that was critical for tumor development as both genetic and pharmacologic inhibition of AR-induced polyamine synthesis enhanced growth inhibition of prostate cancer by supraphysiological androgens. This polyamine reduction lessened negative feedback regulation of S-adenosylmethionine synthase 1 (AMD1), enhancing its utilization of S-adenosylmethionine (SAM), which reduced global protein methylation patterns and expression of the protooncogene MYC. The ODC inhibitor difluoromethylornithine (DFMO) was effective in reduction of polyamines in patients with metastatic CRPC even despite treatment with bipolar androgen therapy, supporting further study of this therapy combination. Thus, the AR is a critical regulator of polyamine synthesis, which may constitute a vulnerability in prostate cancer treated with bipolar androgen therapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE287760 | GEO | 2025/11/05

REPOSITORIES: GEO

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Project description:Polyamines are aliphatic polycations that have emerged as important determinants of cell growth and viability in rapidly proliferating cells, including in the pathogenic protozoan parasite Leishmania donovani. In L. donovani, the polyamine spermidine is synthesized by the successive conversion of ornithine into putrescine (catalyzed by ornithine decarboxylase or ODC) and putrescine into spermidine (catalyzed by spermidine synthase or SPDSYN). Deletion of either ODC (del-odc) or SPDSYN (del-spdsyn) from the L. donovani genome renders these parasites auxotrophic for polyamines and these mutants are impaired in their ability to survive both in culture and within the mammalian host without the addition of exogenous polyamine supplementation. Significantly, del-odc parasites immediately cease proliferation after putrescine is removed from the culture media and perish within two weeks, while spermidine starved del-spdsyn mutants, which retain intracellular putrescine pools, show a slow-growth phenotype, and persist for several weeks in culture. To elucidate the key differences within the proteome of putrescine-starved del-odc cells and spermidine-starved del-spdsyn parasites, a shotgun quantitative proteomics approach was undertaken using TMT labeling and LC-MS/MS analysis. Briefly, three biological replicates each for mid-log phase del-odc and del-spdsyn promastigotes grown in the presence of exogenous putrescine (for del-odc) or spermidine (for del-spdsyn) supplementation were washed to remove the exogenous polyamine supplementation and incubated in polyamine-free media. At 24 and 48 h, cells from each biological replicate were isolated and prepared for tandem mass tag (TMT) labeling and downstream LC-MS/MS analyses. Peptides were identified using a database generated from the reference genome of L. donovani BPK282A1 strain. Changes in relative protein abundance for the polyamine-starved del-odc and del-spdsyn cell lines at 24 and 48 h were calculated by comparing aggregate total reporter ion intensities for each protein to that of the corresponding polyamine-supplemented 0-h timepoint.

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Androgen receptor drives polyamine synthesis creating a vulnerability for prostate cancer

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