In vivo  assessment of increased oxidation of branched-chain amino acids in glioblastoma

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Abstract

Altered branched-chain amino acids (BCAAs) metabolism is a distinctive feature of various cancers and plays an important role in sustaining tumor proliferation and aggressiveness. Despite the therapeutic and diagnostic potentials, the role of BCAA metabolism in cancer and the activities of associated enzymes remain unclear. Due to its pivotal role in BCAA metabolism and rapid cellular transport, hyperpolarized ¹³C-labeled α-ketoisocaproate (KIC), the α-keto acid corresponding to leucine, can assess both BCAA aminotransferase (BCAT) and branched-chain α-keto acid dehydrogenase complex (BCKDC) activities via production of [1- ¹³C]leucine or ¹³CO ₂ (and thus H ¹³CO ₃ ⁻), respectively. Here, we investigated BCAA metabolism of F98 rat glioma model in vivo using hyperpolarized ¹³C-KIC. In tumor regions, we observed a decrease in ¹³C-leucine production from injected hyperpolarized ¹³C-KIC via BCAT compared to the contralateral normal-appearing brain, and an increase in H ¹³CO ₃ ⁻, a catabolic product of KIC through the mitochondrial BCKDC. A parallel ex vivo ¹³C NMR isotopomer analysis following steady-state infusion of [U- ¹³C]leucine to glioma-bearing rats verified the increased oxidation of leucine in glioma tissue. Both the in vivo hyperpolarized KIC imaging and the leucine infusion study indicate that KIC catabolism is upregulated through BCAT/BCKDC and further oxidized via the citric acid cycle in F98 glioma.

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Increase in signal-to-noise ratio of > 10,000 times in liquid-state NMR.

J Ardenkjaer-Larsen, B Fridlund, A Gram … (2011)

A method for obtaining strongly polarized nuclear spins in solution has been developed. The method uses low temperature, high magnetic field, and dynamic nuclear polarization (DNP) to strongly polarize nuclear spins in the solid state. The solid sample is subsequently dissolved rapidly in a suitable solvent to create a solution of molecules with hyperpolarized nuclear spins. The polarization is performed in a DNP polarizer, consisting of a super-conducting magnet (3.35 T) and a liquid-helium cooled sample space. The sample is irradiated with microwaves at approximately 94 GHz. Subsequent to polarization, the sample is dissolved by an injection system inside the DNP magnet. The dissolution process effectively preserves the nuclear polarization. The resulting hyperpolarized liquid sample can be transferred to a high-resolution NMR spectrometer, where an enhanced NMR signal can be acquired, or it may be used as an agent for in vivo imaging or spectroscopy. In this article we describe the use of the method on aqueous solutions of [13C]urea. Polarizations of 37% for 13C and 7.8% for 15N, respectively, were obtained after the dissolution. These polarizations correspond to an enhancement of 44,400 for 13C and 23,500 for 15N, respectively, compared with thermal equilibrium at 9.4 T and room temperature. The method can be used generally for signal enhancement and reduction of measurement time in liquid-state NMR and opens up for a variety of in vitro and in vivo applications of DNP-enhanced NMR.

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Detecting tumor response to treatment using hyperpolarized 13C magnetic resonance imaging and spectroscopy.

Sam E Day, Mikko Kettunen, Ferdia Gallagher … (2007)

Measurements of early tumor responses to therapy have been shown, in some cases, to predict treatment outcome. We show in lymphoma-bearing mice injected intravenously with hyperpolarized [1-(13)C]pyruvate that the lactate dehydrogenase-catalyzed flux of (13)C label between the carboxyl groups of pyruvate and lactate in the tumor can be measured using (13)C magnetic resonance spectroscopy and spectroscopic imaging, and that this flux is inhibited within 24 h of chemotherapy. The reduction in the measured flux after drug treatment and the induction of tumor cell death can be explained by loss of the coenzyme NAD(H) and decreases in concentrations of lactate and enzyme in the tumors. The technique could provide a new way to assess tumor responses to treatment in the clinic.

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Cancer progression by reprogrammed BCAA metabolism in myeloid leukemia

Ayuna Hattori, Makoto Tsunoda, Takaaki Konuma … (2017)

Summary Reprogrammed cellular metabolism is a common characteristic observed in various cancers 1,2 . However, whether metabolic changes directly regulate cancer development and progression remains poorly understood. Here we show that BCAT1, a cytosolic aminotransferase for the branched-chain amino acids (BCAAs), is aberrantly activated and functionally required for chronic myeloid leukemia (CML). BCAT1 is up-regulated during CML progression and promotes BCAA production in leukemia cells by aminating the branched-chain keto acids. Blocking BCAT1 expression or enzymatic activity induces cellular differentiation and impairs the propagation of blast crisis CML (BC-CML) both in vitro and in vivo. Stable isotope tracer experiments combined with NMR-based metabolic analysis demonstrate the intracellular production of BCAAs by BCAT1. Direct supplementation with BCAAs ameliorates the defects caused by BCAT1 knockdown, indicating that BCAT1 exerts its oncogenic function via BCAA production in BC-CML cells. Importantly, BCAT1 expression not only is activated in human BC-CML and de novo acute myeloid leukemia but also predicts disease outcome in patients. As an upstream regulator of BCAT1 expression, we identified Musashi2 (MSI2), an oncogenic RNA binding protein that is required for BC-CML. MSI2 is physically associated with the BCAT1 transcript and positively regulates its protein expression in leukemia. Taken together, this work reveals that altered BCAA metabolism activated through the MSI2-BCAT1 axis drives cancer progression in myeloid leukemia.

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Author and article information

Contributors

Jae Mo Park:

ORCID: http://orcid.org/0000-0002-7404-6971

jaemo.park@utsouthwestern.edu

Journal

Journal ID (nlm-ta): Sci Rep

Journal ID (iso-abbrev): Sci Rep

Title: Scientific Reports

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2045-2322

Publication date (Electronic): 23 January 2019

Publication date PMC-release: 23 January 2019

Publication date Collection: 2019

Volume: 9

Electronic Location Identifier: 340

Affiliations

[1 ]ISNI 0000 0000 9482 7121, GRID grid.267313.2, Advanced Imaging Research Center, , UT Southwestern Medical Center, ; Dallas, TX USA

[2 ]ISNI 0000 0000 9482 7121, GRID grid.267313.2, Department of Biochemistry, , UT Southwestern Medical Center, ; Dallas, TX USA

[3 ]ISNI 0000 0000 9482 7121, GRID grid.267313.2, Department of Internal Medicine, , UT Southwestern Medical Center, ; Dallas, TX USA

[4 ]ISNI 0000 0000 9482 7121, GRID grid.267313.2, Department of Pathology, , UT Southwestern Medical Center, ; Dallas, TX USA

[5 ]ISNI 0000 0000 9482 7121, GRID grid.267313.2, Department of Pharmacology, , UT Southwestern Medical Center, ; Dallas, TX USA

[6 ]ISNI 0000 0001 2151 7939, GRID grid.267323.1, Department of Chemistry and Biochemistry, UT Dallas, ; Richardson, TX USA

[7 ]ISNI 0000 0000 9482 7121, GRID grid.267313.2, Department of Radiology, , UT Southwestern Medical Center, ; Dallas, TX USA

[8 ]ISNI 0000 0001 2151 7939, GRID grid.267323.1, Department of Electrical Engineering, UT Dallas, ; Richardson, TX USA

Author information

Weibo Luo http://orcid.org/0000-0002-1992-0320

A. Dean Sherry http://orcid.org/0000-0001-7150-8301

Jae Mo Park http://orcid.org/0000-0002-7404-6971

Article

Publisher ID: 37390

DOI: 10.1038/s41598-018-37390-0

PMC ID: 6344513

PubMed ID: 30674979

SO-VID: b9edec79-591b-4fa5-b3e2-d3e941144f2e

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 24 October 2018

Date accepted : 4 December 2018

Funding

Funded by: FundRef https://doi.org/10.13039/100000928, Welch Foundation;

Award ID: I-1286

Award ID: I-1903

Award ID: AT-584

Award Recipient : David T. Chuang Weibo Luo A. Dean Sherry

Funded by: FundRef https://doi.org/10.13039/100000062, U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (National Institute of Diabetes & Digestive & Kidney Diseases);

Award ID: R01 DK062306

Award Recipient : David T. Chuang

Funded by: FundRef https://doi.org/10.13039/100009634, Susan G. Komen (Susan G. Komen Breast Cancer Foundation);

Award ID: CCR16376227

Award Recipient : Weibo Luo

Funded by: FundRef https://doi.org/10.13039/100004917, Cancer Prevention and Research Institute of Texas (Cancer Prevention Research Institute of Texas);

Award ID: RR140036

Award ID: RP140021

Award Recipient : Weibo Luo A. Dean Sherry

Funded by: FundRef https://doi.org/10.13039/100000054, U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI);

Award ID: R00 CA168746

Award Recipient : Weibo Luo

Funded by: FundRef https://doi.org/10.13039/100000070, U.S. Department of Health & Human Services | NIH | National Institute of Biomedical Imaging and Bioengineering (NIBIB);

Award ID: P41 EB015908

Award Recipient : A. Dean Sherry

Funded by: FundRef https://doi.org/10.13039/100000050, U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI);

Award ID: R37 HL034557

Award Recipient : A. Dean Sherry

Funded by: UT Southwestern Mobility Foundation Center, The Texas Institute of Brain Injury and Repair

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In vivo assessment of increased oxidation of branched-chain amino acids in glioblastoma

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Most cited references 35

Increase in signal-to-noise ratio of > 10,000 times in liquid-state NMR.

Detecting tumor response to treatment using hyperpolarized 13C magnetic resonance imaging and spectroscopy.

Cancer progression by reprogrammed BCAA metabolism in myeloid leukemia

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Cited by 11

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