Serine and one-carbon metabolisms bring new therapeutic venues in prostate cancer

Abstract

Serine and one-carbon unit metabolisms are essential biochemical pathways implicated in fundamental cellular functions such as proliferation, biosynthesis of important anabolic precursors and in general for the availability of methyl groups. These two distinct but interacting pathways are now becoming crucial in cancer, the de novo cytosolic serine pathway and the mitochondrial one-carbon metabolism. Apart from their role in physiological conditions, such as epithelial proliferation, the serine metabolism alterations are associated to several highly neoplastic proliferative pathologies. Accordingly, prostate cancer shows a deep rearrangement of its metabolism, driven by the dependency from the androgenic stimulus. Several new experimental evidence describes the role of a few of the enzymes involved in the serine metabolism in prostate cancer pathogenesis. The aim of this study is to analyze gene and protein expression data publicly available from large cancer specimens dataset, in order to further dissect the potential role of the abovementioned metabolism in the complex reshaping of the anabolic environment in this kind of neoplasm. The data suggest a potential role as biomarkers as well as in cancer therapy for the genes (and enzymes) belonging to the one-carbon metabolism in the context of prostatic cancer.

p53 regulates expression of nuclear envelope components in cancer cells

“…We recently showed that in PDAC-derived mouse cells p53 controls metabolic pathways by transcriptionally regulating a gene expression programme impinging on aminoacid metabolism [30]. Within this, regulation of methionine uptake appeared to affect the biosynthesis of S-adenosyl-methionine, a major methyl donor, altering the ability of the cell to cope with perturbation of DNA methylation and triggering genomic instability [6,17,30]. Thus, a link between epigenetic regulation of chromatin and metabolism emerged as underlying control mechanism of p53-mediated genomic integrity [27,49].…”

Druggable Metabolic Vulnerabilities Are Exposed and Masked during Progression to Castration Resistant Prostate Cancer

“…Exogenous serine and glycine both provide important building blocks for protein, nucleic acid, and lipids synthesis [ 203 , 204 ]. Many enzymes involved in one-carbon metabolism is AR- or MYC-regulated [ 205 , 206 ], and an overall upregulation in this metabolic pathway plays a crucial role in facilitating PCa progression [ 199 ].…”

Prognostic Significance of Amino Acid Metabolism-Related Genes in Prostate Cancer Retrieved by Machine Learning

“…In prostate cancer, it was recently shown that increased serine and one-carbon pathway metabolism promote a neuroendocrine phenotype, which is the most lethal subtype of castration-resistant prostate cancer [17]. This characteristic represents a targetable vulnerability for prostate cancer [18,19]. In line with these findings, the role of alanine-serine-cysteine transporter 2 (ASCT2, SLC1A5) was studied.…”