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Targeting a Metabolic Vulnerability in Prostate Cancer
Başlık:
Targeting a Metabolic Vulnerability in Prostate Cancer
Yazar:
Affronti, Hayley Catherine, author. (orcid)0000-0001-9751-0629
ISBN:
9780438047723
Yazar Ek Girişi:
Fiziksel Tanımlama:
1 electronic resource (240 pages)
Genel Not:
Source: Dissertation Abstracts International, Volume: 79-10(E), Section: B.
Advisors: Dominic J. Smiraglia Committee members: Mikhail A. Nikiforov; Roberto Pili.
Özet:
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 N 1-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.
Notlar:
School code: 0656
Tüzel Kişi Ek Girişi:
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Yer Numarası | Demirbaş Numarası | Shelf Location | Lokasyon / Statüsü / İade Tarihi |
---|---|---|---|
XX(681036.1) | 681036-1001 | Proquest E-Tez Koleksiyonu | Arıyor... |
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