Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA.
Department of Biomedical Sciences, Texas Tech University Health Sciences Center, Amarillo, Texas, USA.
Prostate. 2022 Jan;82(1):154-166. doi: 10.1002/pros.24256. Epub 2021 Oct 18.
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).
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.
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.
The 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.
代谢重编程现在是癌症的一个公认标志。由于前列腺特异性磷酸酶和张力蛋白同源物缺失于染色体 10 号（Pten）基因条件性敲除（KO）小鼠致癌模型与人类前列腺癌的主要分子缺陷和组织病理学特征非常相似，因此非常适合研究前列腺癌生物学和预防。我们最近通过蛋白质组学和转录组学对该模型进行了大分子分析，表明炎症和髓样抑制性免疫细胞特征占主导地位。在这里，我们对 Pten-KO 前列腺与野生型（WT）对照进行了代谢组学分析，以确定水相代谢物的明显变化，并与 TRAMP 神经内分泌癌（NECa）进行了对比。
对 20-22 周龄同窝/同笼配对的组织特异性条件性 Pten-KO 小鼠前列腺和 WT 前列腺的 3 对组织和 3 对 TRAMP NECa 与 WT（28-31 周）进行了全谱水相代谢物变化的分析，采用亲水相互作用液相色谱-串联质谱法。
与 WT 前列腺相比，Pten-KO 前列腺的嘌呤核苷酸池、胱硫醚、还原型和氧化型谷胱甘肽（GSH、GSSG）以及胆固醇硫酸盐和多胺前体鸟氨酸增加。相反，Pten-KO 前列腺的糖酵解中间产物和磷酸胆碱衍生物、一些氨基酸及其代谢物的浓度降低。生物信息学整合表明，葡萄糖从糖酵解-柠檬酸循环和甘油磷脂生成转向戊糖磷酸循环以产生 NADPH/GSH/GSSG 还原和戊糖部分用于嘌呤和嘧啶核苷酸以及糖基化/葡糖醛酸化，从而显著转移。Pten-KO 模型中明显的精氨酸分解为鸟氨酸与免疫抑制有关。虽然胱硫醚-GSH/GSSG、嘌呤和嘧啶核苷酸池以及葡糖醛酸化也增加，但以牺牲糖酵解-柠檬酸循环为代价，TRAMP NECa 增加了许多氨基酸、甲基供体 S-腺苷甲硫氨酸和磷脂的中间产物，而不增加胆固醇硫酸盐或鸟氨酸。
与 WT 前列腺相比，Pten-KO 前列腺和 TRAMP NECa 的水相代谢组学模式在胱硫醚、GSH/GSSG 氧化还原对和核苷酸的浓度增加以及两种模型中糖酵解-柠檬酸循环的转移方面有相似之处。它们之间的显著代谢差异包括许多氨基酸（蛋白质合成；精氨酸-鸟氨酸/免疫抑制）和胆固醇硫酸盐以及用于表观遗传调节的甲基供体的代谢。
