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 13CO2 (and thus H13CO3−), 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 H13CO3−, a catabolic product of KIC through the mitochondrial BCKDC. A parallel ex 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 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.
Highlights
In tumors, energy dependence on substrates is significantly altered to compensate elevated biosynthesis and bioenergetics needed for tumor proliferation[1]
We used F98 cell line for glioma model. It is histologically classified as an anaplastic glioma, which is pathologically undifferentiated malignant glioma[27,28], and the characteristics of tumor growth are similar with human glioblastoma multiforme (GBM) in overexpression of the epidermal growth factor receptor (EGFR)[28]
ketoisocaproic acid (KIC) can be delivered to intracellular space via monocarboxylic transporter (MCT) and instantly converted to [1-13C]leucine by BCAT24 or to CO2 by branched-chain α-keto acid dehydrogenase complex (BCKDC)
Summary
Energy dependence on substrates is significantly altered to compensate elevated biosynthesis and bioenergetics needed for tumor proliferation[1]. The BCATs catalyze reversible transamination reaction between BCAA and BCKA, the catabolic pathway of BCAAs is the predominant direction in most cell types. Hyperpolarized (HP) [1-13C]KIC was used to assess BCAT-mediated leucine metabolism in the brain in vivo. Previous studies showed that the HP [1-13C]KIC conversion to [1-13C]leucine was correlated with BCAT activity in prostate cancer cells, lymphoma, and normal rat brain. In the prostate cancer cells, elevated BCAT levels resulted in increased production of HP [1-13C]leucine from HP [1-13C]KIC25. Another HP [1-13C]KIC study observed increased [1-13C]leucine conversion in EL4 lymphoma[26]. Butt, et al demonstrated that 13C metabolic imaging using HP 13C KIC is a practical method to access the BCAT activity in vivo in rat brains[24]
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