In vivo assessment of increased oxidation of branched-chain amino acids in glioblastoma
Open Access
- 23 January 2019
- journal article
- research article
- Published by Springer Nature in Scientific Reports
- Vol. 9 (1) , 340
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, hyperpolarized13C-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 or13CO2(and thus H13CO3−), respectively. Here, we investigated BCAA metabolism of F98 rat glioma modelin vivousing hyperpolarized13C-KIC. In tumor regions, we observed a decrease in13C-leucine production from injected hyperpolarized13C-KIC via BCAT compared to the contralateral normal-appearing brain, and an increase in H13CO3−, a catabolic product of KIC through the mitochondrial BCKDC. A parallelex vivo13C 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 thein vivohyperpolarized 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.Keywords
Funding Information
- Welch Foundation (I-1286, I-1903, AT-584)
- U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK062306)
- Susan G. Komen (CCR16376227)
- Cancer Prevention and Research Institute of Texas (RR140036, RP140021)
- U.S. Department of Health & Human Services | NIH | National Cancer Institute (R00 CA168746)
- U.S. Department of Health & Human Services | NIH | National Institute of Biomedical Imaging and Bioengineering (P41 EB015908)
- U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (R37 HL034557)
- UT Southwestern Mobility Foundation Center, The Texas Institute of Brain Injury and Repair
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