Dietary folate levels alter the kinetics and molecular mechanism of prostate cancer recurrence in the CWR22 model

Abstract

Folate impacts the genome and epigenome by feeding into one-carbon metabolism to produce critical metabolites, deoxythymidine monophosphate and s-adenosylmethionine. The impact of folate exposure and intervention timing on cancer progression remains controversial. Due to polyamine metabolism’s extraordinary biosynthetic flux in prostate cancer (CaP) we demonstrated androgen stimulated CaP is susceptible to dietary folate deficiency. We hypothesized dietary folate levels may also affect castration recurrent CaP. We used the CWR22 human xenograft model which recurs following androgen withdrawal. Engrafted mice were fed a folate depleted or supplemented diet beginning at androgen withdrawal, or prior to xenograft implantation. Both folate depletion and supplementation at the time of withdrawal significantly decreased recurrence incidence. Folate supplementation prior to xenograft implantation increased time to recurrence, suggesting a protective role. By contrast, folate depleted recurrent tumors exhibited transcriptional adaptive responses that maintained high polyamine levels at the expense of increased DNA damage and DNA methylation alterations. Mining of publically available data demonstrated folate related pathways are exceptionally dysregulated in human CaP, which correlated with decreased time to biochemical recurrence. These findings highlight the potential for novel therapeutic interventions that target these metabolic pathways in CaP and provide a rationale to apply such strategies alongside androgen withdrawal.

Inhibition of the aryl hydrocarbon receptor/polyamine biosynthesis axis suppresses multiple myeloma

“…Since our previous data revealed that AHR controls polyamine biosynthesis, we decided to assess the degree to which polyamine biosynthesis gene expression correlates with patient survival. To this end, we created a polyamine biosynthesis score by summing the expression levels of the signature enzymes for polyamine biosynthesis (AZIN1, OAZ1, OAZ2, ODC1, SMS, SRM, and AMD1) as previously described for a different gene expression set (89). We analyzed patient survival in relation to this score.…”

Pharmacological polyamine catabolism upregulation with methionine salvage pathway inhibition as an effective prostate cancer therapy

“…Previous work revealed that prostate cancer (CaP) is exquisitely sensitive to perturbation of polyamine metabolism and connected pathways due to high polyamine metabolic flux [9][10][11]13 . These studies demonstrated that the prostate relies heavily on the methionine salvage pathway to survive and that MTAP inhibition blocks LNCaP xenograft growth when given at the time of xenograft implantation 9 .…”

“…Ultra-performance liquid chromatography for polyamines. Ultra-Performance liquid chromatography analyses for polyamines were carried out similarly to previously described methods [10][11][12][13] with adjustments made to the flow rate, gradient, and column indicated below. Acetylated polyamines were extracted from media as previously described 10 .…”

“…The high rate of secretion of acetylated polyamines into the prostatic epithelial lumen makes prostate epithelial cells exquisitely sensitive to perturbations of connected pathways [9][10][11][12][13] . This enhanced polyamine metabolic flux is driven by the activity of spermidine/spermine N1-acetyltransferase (SSAT) which acetylates polyamines to facilitate their secretion into the lumen [14][15][16] ( Fig.…”

“…The high level of polyamine biosynthesis in prostate places added strain on connected pathways, including one-carbon metabolism composed of the methionine cycle and folate metabolism, which are critical for production of SAM and nucleotide pools, respectively [9][10][11][12][13] . Prostate cells are sensitive to dietary folate deficiency in the transgenic adenoma of mouse prostate cancer (TRAMP) model 11 and the CWR22 human xenograft model of CRPC 13 , due to increased acetylated polyamine export. The methionine salvage pathway (MSP) plays a critical role in helping to relieve metabolic strain by recycling the one-carbon unit, 5′methylthioadenosine (MTA), lost to polyamine biosynthesis back to the methionine cycle (Fig.…”