Sun Jinny, Bok Robert A, DeLos Santos Justin, Upadhyay Deepti, DeLos Santos Romelyn, Agarwal Shubhangi, Van Criekinge Mark, Vigneron Daniel B, Aggarwal Rahul, Peehl Donna M, Kurhanewicz John, Sriram Renuka
Graduate Program in Bioengineering, University of California, Berkeley and University of California, San Francisco, CA 94143, USA.
Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA 94143, USA.
Metabolites. 2021 Feb 26;11(3):139. doi: 10.3390/metabo11030139.
Currently, no clinical methods reliably predict the development of castration-resistant prostate cancer (CRPC) that occurs almost universally in men undergoing androgen deprivation therapy. Hyperpolarized (HP) C magnetic resonance imaging (MRI) could potentially detect the incipient emergence of CRPC based on early metabolic changes. To characterize metabolic shifts occurring upon the transition from androgen-dependent to castration-resistant prostate cancer (PCa), the metabolism of [U-C]glucose and [U-C]glutamine was analyzed by nuclear magnetic resonance spectroscopy. Comparison of steady-state metabolite concentrations and fractional enrichment in androgen-dependent LNCaP cells and transgenic adenocarcinoma of the murine prostate (TRAMP) murine tumors versus castration-resistant PC-3 cells and treatment-driven CRPC TRAMP tumors demonstrated that CRPC was associated with upregulation of glycolysis, tricarboxylic acid metabolism of pyruvate; and glutamine, glutaminolysis, and glutathione synthesis. These findings were supported by C isotopomer modeling showing increased flux through pyruvate dehydrogenase (PDH) and anaplerosis; enzymatic assays showing increased lactate dehydrogenase, PDH and glutaminase activity; and oxygen consumption measurements demonstrating increased dependence on anaplerotic fuel sources for mitochondrial respiration in CRPC. Consistent with ex vivo metabolomic studies, HP [1-C]pyruvate distinguished androgen-dependent PCa from CRPC in cell and tumor models based on significantly increased HP [1-C]lactate.
目前，尚无临床方法能够可靠地预测去势抵抗性前列腺癌（CRPC）的发生，这种癌症几乎在接受雄激素剥夺治疗的男性中普遍出现。超极化（HP）碳磁共振成像（MRI）有可能基于早期代谢变化检测到CRPC的初期出现。为了表征从雄激素依赖型前列腺癌向去势抵抗性前列腺癌（PCa）转变过程中发生的代谢变化，通过核磁共振波谱分析了[U-¹³C]葡萄糖和[U-¹³C]谷氨酰胺的代谢情况。对雄激素依赖型LNCaP细胞和小鼠前列腺转基因腺癌（TRAMP）小鼠肿瘤与去势抵抗性PC-3细胞以及治疗诱导的CRPC TRAMP肿瘤中的稳态代谢物浓度和丰度分数进行比较，结果表明CRPC与糖酵解、丙酮酸的三羧酸代谢、谷氨酰胺、谷氨酰胺分解和谷胱甘肽合成的上调有关。¹³C同位素异构体建模显示通过丙酮酸脱氢酶（PDH）和回补反应的通量增加，酶促分析显示乳酸脱氢酶、PDH和谷氨酰胺酶活性增加，以及耗氧量测量表明CRPC中线粒体呼吸对回补燃料来源的依赖性增加，这些结果支持了上述发现。与体外代谢组学研究一致，基于显著增加的HP [¹³C]乳酸，HP [¹³C]丙酮酸在细胞和肿瘤模型中区分了雄激素依赖型PCa和CRPC。
