title: The feasibility of assessing branched-chain amino acid metabolism in cellular models of prostate cancer with hyperpolarized [1-(13)C]-ketoisocaproate.
abstract: Recent advancements in the field of hyperpolarized (13)C magnetic resonance spectroscopy (MRS) have yielded powerful techniques capable of real-time analysis of metabolic pathways. These non-invasive methods have increasingly shown application in impacting disease diagnosis and have further been employed in mechanistic studies of disease onset and progression. Our goals were to investigate branched-chain aminotransferase (BCAT) activity in prostate cancer with a novel molecular probe, hyperpolarized [1-(13)C]-2-ketoisocaproate ([1-(13)C]-KIC), and explore the potential of branched-chain amino acid (BCAA) metabolism to serve as a biomarker. Using traditional spectrophotometric assays, BCAT enzymatic activities were determined in vitro for various sources of prostate cancer (human, transgenic adenocarcinoma of the mouse prostate (TRAMP) mouse and human cell lines). These preliminary studies indicated that low levels of BCAT activity were present in all models of prostate cancer but enzymatic levels are altered significantly in prostate cancer relative to healthy tissue. The MR spectroscopic studies were conducted with two cellular models (PC-3 and DU-145) that exhibited levels of BCAA metabolism comparable to the human disease state. Hyperpolarized [1-(13)C]-KIC was administered to prostate cancer cell lines, and the conversion of [1-(13)C]-KIC to the metabolic product, [1-(13)C]-leucine ([1-(13)C]-Leu), could be monitored via hyperpolarized (13)C MRS.
authors.affiliation: Department of Chemistry & Biochemistry, San Francisco State University, San Francisco, CA 94132, USA. Electronic address: klbillin@sfsu.edu.
authors.forename: Kelvin L
authors.initials: KL
authors.lastname: Billingsley
authors.affiliation: Department of Radiology, Stanford University, Stanford, CA 94305, USA.
authors.forename: Jae Mo
authors.initials: JM
authors.lastname: Park
authors.affiliation: Department of Radiology, Stanford University, Stanford, CA 94305, USA; Neuroscience Program, SRI International, Menlo Park, CA 94025, USA.
authors.forename: Sonal
authors.initials: S
authors.lastname: Josan
authors.affiliation: Applied Sciences Laboratory, GE Healthcare, Menlo Park, CA 94025, USA.
authors.forename: Ralph
authors.initials: R
authors.lastname: Hurd
authors.affiliation: Department of Diagnostic Radiology and Nuclear Medicine, University of Maryland-Baltimore, Baltimore, MD 21201, USA.
authors.forename: Dirk
authors.initials: D
authors.lastname: Mayer
authors.affiliation: Department of Chemistry, Oberlin College, Oberlin, OH 44074, USA.
authors.forename: Eleanor
authors.initials: E
authors.lastname: Spielman-Sun
authors.affiliation: Department of Electrical Engineering, Stanford University, Stanford, CA 94305, USA.
authors.forename: Dwight G
authors.initials: DG
authors.lastname: Nishimura
authors.affiliation: Department of Urology, Stanford University, Stanford, CA 94305, USA.
authors.forename: James D
authors.initials: JD
authors.lastname: Brooks
authors.affiliation: Department of Radiology, Stanford University, Stanford, CA 94305, USA; Department of Electrical Engineering, Stanford University, Stanford, CA 94305, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Spielman
mesh_terms: D000597:Amino Acids, Branched-Chain / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D045744:Cell Line, Tumor; D005240:Feasibility Studies; D006801:Humans; D007651:Keto Acids / Q000493:pharmacokinetics*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D008297:Male; D057054:Molecular Imaging / Q000379:methods; D011471:Prostatic Neoplasms / Q000175:diagnosis / Q000378:metabolism*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D000637:Transaminases / Q000378:metabolism*
chemical_list: D000597:Amino Acids, Branched-Chain; D014408:Biomarkers, Tumor; D007651:Keto Acids; D019275:Radiopharmaceuticals; C013082:alpha-ketoisocaproic acid; D000637:Transaminases; C019798:branched-chain-amino-acid transaminase
keywords: Branched-chain aminotransferase; Dynamic nuclear polarization; Hyperpolarized carbon-13; Magnetic resonance spectroscopy/spectroscopic imaging; Prostate cancer