Abstract | BACKGROUND: Metabolic 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). METHODS: Three 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. RESULTS: The 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. CONCLUSIONS:
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Authors | Sangyub Kim, Li Li, Jinhui Zhang, Cheng Jiang, Junxuan Lü |
Journal | The Prostate
(Prostate)
Vol. 82
Issue 1
Pg. 154-166
(01 2022)
ISSN: 1097-0045 [Electronic] United States |
PMID | 34662447
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Copyright | © 2021 The Authors. The Prostate published by Wiley Periodicals LLC. |
Chemical References |
- Biomarkers
- Receptors, Tumor Necrosis Factor, Member 25
- Tnfrsf25 protein, mouse
- PTEN Phosphohydrolase
- Pten protein, mouse
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Topics |
- Animals
- Biomarkers
(analysis)
- Carcinoma, Neuroendocrine
(metabolism, pathology)
- Chromatography, Liquid
(methods)
- Disease Models, Animal
- Male
- Metabolomics
(methods)
- Mice
- Mice, Knockout
- PTEN Phosphohydrolase
(metabolism)
- Prostate
(metabolism, pathology)
- Prostatic Neoplasms
(metabolism, pathology)
- Receptors, Tumor Necrosis Factor, Member 25
(metabolism)
- Tandem Mass Spectrometry
(methods)
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