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

Jinny Sun,Shubhangi Agarwal,Justin Delos Santos,Mark Van Criekinge,John Kurhanewicz,Deepti Upadhyay,Romelyn Delos Santos,Donna M Peehl,Daniel B Vigneron,Robert A Bok,Rahul Aggarwal,Renuka Sriram

doi:10.3390/metabo11030139

Jinny Sun, Shubhangi Agarwal + Show 10 more

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https://doi.org/10.3390/metabo11030139

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Abstract

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.

Highlights

Versus castration-resistant prostate cancer (CRPC), LNCaP and PC-3 cells were labeled with [U-13 C]glucose or [U-13 C]glutamine in vitro, and androgen-dependent PCa (ADPC) and CRPC Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) tumors were labeled in vivo in mice infused with [U-13 C]glucose or [U-13 C]glutamine
Representative 1D 1 H spectra with water presaturation clearly highlight the differences in the metabolic flux of glucose and glutamine between the ADPC versus CRPC cell lines (Figure S1A,B) and TRAMP
Zoomed region indicates glutamate C4 region with vertical scale increased by 2-fold. 2D 1 H-13 C HSQC of LNCaP and PC-3 cell extracts labeled with C, [U-13 C]glucose and D, [U-13 C]glutamine

Summary

Introduction

Androgen deprivation therapy (ADT) is the cornerstone of treatment for men with recurrent or metastatic prostate cancer (PCa). Almost all patients eventually stop responding to ADT and develop castration-resistant prostate cancer (CRPC) [1]. Clinical diagnosis of CRPC is based on a significant increase in tumor burden or metastasis detected using computed tomography (CT) scans, bone scintigraphy or magnetic resonance imaging (MRI), and/or rising serum prostate-specific antigen (PSA) levels [2]. No reliable clinical or non-invasive imaging methods can predict the development of CRPC, which is critical in guiding treatment decisions in men with advanced PCa. Early detection

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