Glutamine synthetase expression rescues human dendritic cell survival in a glutamine-deprived environment

TY - JOUR

T1 - Glutamine synthetase expression rescues human dendritic cell survival in a glutamine-deprived environment

AU - Schoeppe, Robert

AU - Babl, Nathalie

AU - Decking, Sonja-Maria

AU - Schönhammer, Gabriele

AU - Siegmund, Andreas

AU - Bruss, Christina

AU - Dettmer, Katja

AU - Oefner, Peter J

AU - Frick, Linus

AU - Weigert, Anna

AU - Jantsch, Jonathan

AU - Herr, Wolfgang

AU - Rehli, Michael

AU - Renner, Kathrin

AU - Kreutz, Marina

N1 - Copyright © 2023 Schoeppe, Babl, Decking, Schönhammer, Siegmund, Bruss, Dettmer, Oefner, Frick, Weigert, Jantsch, Herr, Rehli, Renner and Kreutz.

PY - 2023

Y1 - 2023

N2 - INTRODUCTION: Glutamine 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.METHODS: Different 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.RESULTS: The 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.DISCUSSION: Our 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.

AB - INTRODUCTION: Glutamine 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.METHODS: Different 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.RESULTS: The 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.DISCUSSION: Our 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.

U2 - 10.3389/fonc.2023.1120194

DO - 10.3389/fonc.2023.1120194

M3 - SCORING: Journal article

C2 - 36741028

VL - 13

SP - 1120194

JO - FRONT ONCOL

JF - FRONT ONCOL

SN - 2234-943X

ER -