Branched-chain ketoacids secreted by glioblastoma cells via MCT1 modulate macrophage phenotype
2017
Authors: Silva LS, Poschet G, Nonnenmacher Y, Becker HM, Sapcariu S, Gaupel AC, Schlotter M, Wu Y, Kneisel N, Seiffert M, Hell R, Hiller K, Lichter P, Radlwimmer B
CellNetworks People: Hell Rüdiger
Journal: EMBO Rep. 2017 Dec;18(12):2172-2185. doi: 10.15252/embr.201744154

Elevated amino acid catabolism is common to many cancers. Here, we show that glioblastoma are excreting large amounts of branched-chain ketoacids (BCKAs), metabolites of branched-chain amino acid (BCAA) catabolism. We show that efflux of BCKAs, as well as pyruvate, is mediated by the monocarboxylate transporter 1 (MCT1) in glioblastoma. MCT1 locates in close proximity to BCKA-generating branched-chain amino acid transaminase 1, suggesting possible functional interaction of the proteins. Using in vitro models, we demonstrate that tumor-excreted BCKAs can be taken up and re-aminated to BCAAs by tumor-associated macrophages. Furthermore, exposure to BCKAs reduced the phagocytic activity of macrophages. This study provides further evidence for the eminent role of BCAA catabolism in glioblastoma by demonstrating that tumor-excreted BCKAs might have a direct role in tumor immune suppression. Our data further suggest that the anti-proliferative effects of MCT1 knockdown observed by others might be related to the blocked excretion of BCKAs.