Two parallel pathways connect glutamine metabolism and mTORC1 activity to regulate glutamoptosis
2 UPO - Universidad Pablo de Olavide [Sevilla]
3 BaRITOn - Bordeaux Research In Translational Oncology [Bordeaux]
4 CAM - University of Cambridge [Cambridge, UK]
5 CSHL - Cold Spring Harbor Laboratory
6 UB - Université de Bordeaux
7 ACTION - Actions for OnCogenesis understanding and Target Identification in ONcology
8 Institut Bergonié [Bordeaux]
9 Universidad de Sevilla = University of Seville = Université de Seville
10 Physiopathologie du cancer du foie
11 CR-UK Beatson Institute - Institute of Cancer Sciences [Glasgow, UK]
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Résumé
Abstract Glutamoptosis is the induction of apoptotic cell death as a consequence of the aberrant activation of glutaminolysis and mTORC1 signaling during nutritional imbalance in proliferating cells. The role of the bioenergetic sensor AMPK during glutamoptosis is not defined yet. Here, we show that AMPK reactivation blocks both the glutamine-dependent activation of mTORC1 and glutamoptosis in vitro and in vivo. We also show that glutamine is used for asparagine synthesis and the GABA shunt to produce ATP and to inhibit AMPK, independently of glutaminolysis. Overall, our results indicate that glutamine metabolism is connected with mTORC1 activation through two parallel pathways: an acute alpha-ketoglutarate-dependent pathway; and a secondary ATP/AMPK-dependent pathway. This dual metabolic connection between glutamine and mTORC1 must be considered for the future design of therapeutic strategies to prevent cell growth in diseases such as cancer.