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

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 ?-ketoisocaproate (KIC), the ?-keto acid corresponding to leucine, can assess both BCAA aminotransferase (BCAT) and branched-chain ?-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 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.

SUBMITTER: Suh EH

PROVIDER: S-EPMC6344513 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Project description:BackgroundCirculating branched-chain amino acid (BCAA) levels reflect metabolic health and dietary intake. However, associations with breast cancer are unclear.MethodsWe evaluated circulating BCAA levels and breast cancer risk within the Nurses' Health Study (NHS) and NHSII (1997 cases and 1997 controls). A total of 592 NHS women donated 2 blood samples 10 years apart. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) of breast cancer risk in multivariable logistic regression models. We conducted an external validation in 1765 cases in the Women's Health Study (WHS). All statistical tests were 2-sided.ResultsAmong NHSII participants (predominantly premenopausal at blood collection), elevated circulating BCAA levels were associated with lower breast cancer risk (eg, isoleucine highest vs lowest quartile, multivariable OR = 0.86, 95% CI = 0.65 to 1.13, P trend = .20), with statistically significant linear trends among fasting samples (eg, isoleucine OR = 0.74, 95% CI = 0.53 to 1.05, P trend = .05). In contrast, among postmenopausal women, proximate measures (<10 years from blood draw) were associated with increased breast cancer risk (eg, isoleucine OR = 1.63, 95% CI = 1.12 to 2.39, P trend = .01), with stronger associations among fasting samples (OR = 1.73, 95% CI = 1.15 to 2.61, P trend = .01). Distant measures (10-20 years since blood draw) were not associated with risk. In the WHS, a positive association was observed for distant measures of leucine among postmenopausal women (OR = 1.23, 95% CI = 0.96 to 1.58, P trend = .04).ConclusionsNo statistically significant associations between BCAA levels and breast cancer risk were consistent across NHS and WHS or NHSII and WHS. Elevated circulating BCAA levels were associated with lower breast cancer risk among predominantly premenopausal NHSII women and higher risk among postmenopausal women in NHS but not in the WHS. Additional studies are needed to understand this complex relationship.

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

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