Resistance to Androgen Deprivation Leads to Altered Metabolism in Human and Murine Prostate Cancer Cell and Tumor Models

Metabolites

RobertA Bok¹  Deepti Upadhyay¹  Renuka Sriram¹  Shubhangi Agarwal¹  Justin DeLos Santos¹  DonnaM Peehl¹  Mark Van Criekinge¹  Romelyn DeLos Santos¹  DanielB Vigneron¹  John Kurhanewicz¹  Jinny Sun²  Rahul Aggarwal³ 

[1] Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA 94143, USA;Graduate Program in Bioengineering, University of California, Berkeley and University of California, San Francisco, CA 94143, USA;Hematology/Oncology, University of California, San Francisco, CA 94143, USA;

关键词: metabolism;    prostate cancer;    castration-resistant;    androgen-dependent;    TRAMP;    magnetic resonance;   

DOI  :  10.3390/metabo11030139

来源: DOAJ

【 摘 要 】

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) ¹³C 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-¹³C]glucose and [U-¹³C]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 ¹³C 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 [1-¹³C]pyruvate distinguished androgen-dependent PCa from CRPC in cell and tumor models based on significantly increased HP [1-¹³C]lactate.

【 授权许可】

Unknown