Aqueous metabolome of tissue-specific conditional Pten-knockout mouse prostate cancer and TRAMP neuroendocrine carcinoma.

Abstract

BackgroundMetabolic reprograming is now a recognized hallmark of cancer. The prostate‐specific phosphatase and tensin homolog deleted on chromosome 10 (Pten) gene‐conditional knockout (KO) mouse carcinogenesis model is highly desirable for studying prostate cancer biology and prevention due to its close resemblance of primary molecular defects and histopathological features of human prostate cancer. We have recently published macromolecular profiling of this model by proteomics and transcriptomics, denoting a preeminence of inflammation and myeloid suppressive immune cell features. Here, we performed metabolomic analyses of Pten‐KO prostate versus wild type (WT) counterpart for discernable changes in the aqueous metabolites and contrasted to those in the TRAMP neuroendocrine carcinoma (NECa).MethodsThree matched pairs of tissue‐specific conditional Pten‐KO mouse prostate and WT prostate of litter/cage‐mates at 20–22 weeks of age and three pairs of TRAMP NECa versus WT (28–31 weeks) were profiled for their global aqueous metabolite changes, using hydrophilic interaction liquid chromatography‐tandem mass spectrometry.ResultsThe Pten‐KO prostate increased purine nucleotide pools, cystathionine, and both reduced and oxidized glutathione (GSH, GSSG), and gluconate/glucuronate species in addition to cholesteryl sulfate and polyamine precursor ornithine. On the contrary, Pten‐KO prostate contained diminished pools of glycolytic intermediates and phosphorylcholine derivatives, select amino acids, and their metabolites. Bioinformatic integration revealed a significant shunting of glucose away from glycolysis‐citrate cycle and glycerol‐lipid genesis to pentose phosphate cycle for NADPH/GSH/GSSG redox and pentose moieties for purine and pyrimidine nucleotides, and glycosylation/glucuronidation. Implicit arginine catabolism to ornithine was consistent with immunosuppression in Pten‐KO model. While also increased in cystathionine‐GSH/GSSG, purine, and pyrimidine nucleotide pools and glucuronidation at the expense of glycolysis‐citrate cycle, the TRAMP NECa increased abundance of many amino acids, methyl donor S‐adenosyl‐methionine, and intermediates for phospholipids without increasing cholesteryl sulfate or ornithine.ConclusionsThe aqueous metabolomic patterns in Pten‐KO prostate and TRAMP NECa shared similarities in the greater pools of cystathionine, GSH/GSSG redox pair, and nucleotides and shunting away from glycolysis‐citrate cycle in both models. Remarkable metabolic distinctions between them included metabolisms of many amino acids (protein synthesis; arginine‐ornithine/immune suppression) and cholesteryl sulfate and methylation donor for epigenetic regulations.