Metabolic recycling of ammonia via glutamate dehydrogenase supports breast cancer biomass
Menée in vitro et in vivo sur des modèles de cancer du sein, cette étude met en évidence des mécanismes par lesquels l'ammoniac accumulé dans le microenvironnement tumoral constitue une source d'azote pour le métabolisme des cellules cancéreuses
Ammonia, often considered a metabolic waste product, can be recycled to build new amino acids. Rapidly proliferating cells produce extracellular nitrogen. Spinelli et al. used metabolic tracing of 15N to follow the fate of extracellular ammonia and its incorporation into more than 200 components of the nitrogen metabolome (see the Perspective by Dang). Accumulation of ammonia enabled glutamate dehydrogenase to function in reductive amination, which allowed incorporation of nitrogen from ammonia back into amino acids. Experiments in mice also showed incorporation of ammonia into glutamate, aspartate, and proline.Science, this issue p. 941; see also p. 862 Ammonia is a ubiquitous by-product of cellular metabolism; however, the biological consequences of ammonia production are not fully understood, especially in cancer. We found that ammonia is not merely a toxic waste product but is recycled into central amino acid metabolism to maximize nitrogen utilization. In our experiments, human breast cancer cells primarily assimilated ammonia through reductive amination catalyzed by glutamate dehydrogenase (GDH); secondary reactions enabled other amino acids, such as proline and aspartate, to directly acquire this nitrogen. Metabolic recycling of ammonia accelerated proliferation of breast cancer. In mice, ammonia accumulated in the tumor microenvironment and was used directly to generate amino acids through GDH activity. These data show that ammonia is not only a secreted waste product but also a fundamental nitrogen source that can support tumor biomass.
Science 2017