Androgen receptor drives polyamine synthesis creating a vulnerability for prostate cancer

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.