Targeting a Metabolic Vulnerability in Prostate Cancer

Prostatic epithelial cells secrete high levels of acetylated polyamines into the prostatic lumen, which are an essential component of the prostatic fluid and play an important role in fertilization. This distinctive characteristic places added strain on connected pathways, including folate metabolism and the methionine cycle, to maintain nucleotide and S-adenosylmethionine (SAM) pools, respectively. More importantly, this stress is increased in prostate cancer (CaP) due to increased polyamine biosynthesis, DNA synthesis, and proliferation. The metabolic flux is driven by the activity of spermidine/spermine N1-acetyltransferase (SSAT) which acetylates the polyamines leading to their secretion into the lumen, and thereby driving demand for biosynthesis of polyamines. To overcome this stress, the methionine salvage pathway (MSP) recycles the one-carbon unit lost to polyamine biosynthesis back to the methionine cycle, allowing for replenishment of methionine and SAM pools. The rate-limiting enzyme involved in this process is methylthioadenosine phosphorylase (MTAP). De novo synthesis of methionine depends on the availability of folate, acquired from the diet, which acts as a carrier for one-carbon units through one-carbon metabolism. The one-carbon unit, donated from serine, can be contributed to methionine biosynthesis, which can then be used to produce SAM. Previous results from our lab have shown that CaP is uniquely sensitive to dietary folate restriction in the Transgenic Adenoma of the Mouse Prostate Cancer (TRAMP) model of androgen sensitive CaP and this sensitivity is a result of enhanced polyamine flux. Based on these results we predicted that castration recurrent prostate cancer (CRPC) may also be sensitive to dietary folate restriction. In this work, we show that recurrence in a mouse model of CRPC is also sensitive to dietary folate interventions. Furthermore, we found that CaP maintains SAM pools and polyamine biosynthetic flux despite folate depletion, and that this correlates with expression of MTAP. Next, we will show that CaP relies on the MSP to relieve the strain caused by high polyamine biosynthesis and that both genetic and pharmacological inhibition of MTAP blocks CaP xenograft growth. Furthermore, we hypothesized that this dependence can be enhanced by increasing the activity of SSAT. Finally, the results reveal that this novel combination of MTAP inhibition alongside SSAT upregulation synergistically blocks CaP growth in vitro and in vivo, and induces apoptosis in human samples tested in an ex vivo system. This combination treatment ultimately impacts polyamines, SAM pools, nucleotides, oxidative stress and potentially fatty acid synthesis. Altogether our work reveals a unique metabolic point of leverage in CaP and provides 3 different therapeutic approaches that leverage a metabolic vulnerability in CaP cells.

Grantor dc:publisher

State University of New York at Buffalo

Year dc:date.issued

2018

Author dc:creator

• Affronti, Hayley; 0000-0001-9751-0629

Contributors dc:contributor

• Smiraglia, Dominic
• Roswell Park

• molecular biology
• cellular biology
• biochemistry
• cancer sciences

Statement dc:rights

• Users of works found in University at Buffalo Institutional Repository (UBIR) are responsible for identifying and contacting the copyright owner for permission to reuse. University at Buffalo Libraries do not manage rights for copyright-protected works and cannot assist with permissions.
• Copyright retained by author.

Language dc:language

eng

Handle dc:identifier

http://hdl.handle.net/10477/77922

OAI record oai:identifier

https://ubir.buffalo.edu/oai/request?verb=GetRecord&metadataPrefix=qdc&identifier=oai%3Aubir.buffalo.edu%3A10477%2F77922