Schoeppe, Robert and Babl, Nathalie and Decking, Sonja-Maria and Schoenhammer, Gabriele and Siegmund, Andreas and Bruss, Christina and Dettmer, Katja and Oefner, Peter J. and Frick, Linus and Weigert, Anna and Jantsch, Jonathan and Herr, Wolfgang and Rehli, Michael and Renner, Kathrin and Kreutz, Marina (2023) Glutamine synthetase expression rescues human dendritic cell survival in a glutamine-deprived environment. FRONTIERS IN ONCOLOGY, 13: 1120194. ISSN 2234-943X,
Full text not available from this repository. (Request a copy)Abstract
IntroductionGlutamine deficiency is a well-known feature of the tumor environment. Here we analyzed the impact of glutamine deprivation on human myeloid cell survival and function. MethodsDifferent types of myeloid cells were cultured in the absence or presence of glutamine and/or with L-methionine-S-sulfoximine (MSO), an irreversible glutamine synthetase (GS) inhibitor. GS expression was analyzed on mRNA and protein level. GS activity and the conversion of glutamate to glutamine by myeloid cells was followed by 13C tracing analyses. ResultsThe absence of extracellular glutamine only slightly affected postmitotic human monocyte to dendritic cell (DC) differentiation, function and survival. Similar results were obtained for monocyte-derived macrophages. In contrast, proliferation of the monocytic leukemia cell line THP-1 was significantly suppressed. While macrophages exhibited high constitutive GS expression, glutamine deprivation induced GS in DC and THP-1. Accordingly, proliferation of THP-1 was rescued by addition of the GS substrate glutamate and 13C tracing analyses revealed conversion of glutamate to glutamine. Supplementation with the GS inhibitor MSO reduced the survival of DC and macrophages and counteracted the proliferation rescue of THP-1 by glutamate. DiscussionOur results show that GS supports myeloid cell survival in a glutamine poor environment. Notably, in addition to suppressing proliferation and survival of tumor cells, the blockade of GS also targets immune cells such as DCs and macrophages.
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