Dietary folate levels alter the kinetics and molecular mechanism of prostate cancer recurrence in the CWR22 model
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Hayley C. Affronti1, Mark D. Long1, Spencer R. Rosario1, Bryan M. Gillard2, Ellen Karasik2, Christoph S. Boerlin1, Anthony J. Pellerite1, Barbara A. Foster2, Kristopher Attwood3, Roberto Pili4, John H. Wilton2, Moray J. Campbell5 and Dominic J. Smiraglia1
1Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY, USA
2Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY, USA
3Department of Biostatistics, Roswell Park Cancer Institute, Buffalo, NY, USA
4Department of Hematology and Oncology, Indiana University, Indianapolis, IN, USA
5College of Pharmacy, Pharmaceutics and Pharmaceutical Chemistry, The Ohio State University, Columbus, OH, USA
Dominic J. Smiraglia, email: [email protected]
Keywords: castration recurrent prostate cancer, androgen withdrawal, folate, one-carbon metabolism, polyamine metabolism
Received: October 06, 2017 Accepted: October 10, 2017 Published: October 20, 2017
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.
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