TY - JOUR
T1 - mTORC1 regulates cell survival under glucose starvation through 4EBP1/2-mediated translational reprogramming of fatty acid metabolism
AU - Levy, Tal
AU - Voeltzke, Kai
AU - Hruby, Laura
AU - Alasad, Khawla
AU - Bas, Zuelal
AU - Snaebjörnsson, Marteinn
AU - Marciano, Ran
AU - Scharov, Katerina
AU - Planque, Mélanie
AU - Vriens, Kim
AU - Christen, Stefan
AU - Funk, Cornelius M.
AU - Hassiepen, Christina
AU - Kahler, Alisa
AU - Heider, Beate
AU - Picard, Daniel
AU - Lim, Jonathan K.M.
AU - Stefanski, Anja
AU - Bendrin, Katja
AU - Vargas-Toscano, Andres
AU - Kahlert, Ulf D.
AU - Stühler, Kai
AU - Remke, Marc
AU - Elkabets, Moshe
AU - Grünewald, Thomas G.P.
AU - Reichert, Andreas S.
AU - Fendt, Sarah Maria
AU - Schulze, Almut
AU - Reifenberger, Guido
AU - Rotblat, Barak
AU - Leprivier, Gabriel
N1 - Publisher Copyright:
© The Author(s) 2024.
PY - 2024/12/1
Y1 - 2024/12/1
N2 - Energetic stress compels cells to evolve adaptive mechanisms to adjust their metabolism. Inhibition of mTOR kinase complex 1 (mTORC1) is essential for cell survival during glucose starvation. How mTORC1 controls cell viability during glucose starvation is not well understood. Here we show that the mTORC1 effectors eukaryotic initiation factor 4E binding proteins 1/2 (4EBP1/2) confer protection to mammalian cells and budding yeast under glucose starvation. Mechanistically, 4EBP1/2 promote NADPH homeostasis by preventing NADPH-consuming fatty acid synthesis via translational repression of Acetyl-CoA Carboxylase 1 (ACC1), thereby mitigating oxidative stress. This has important relevance for cancer, as oncogene-transformed cells and glioma cells exploit the 4EBP1/2 regulation of ACC1 expression and redox balance to combat energetic stress, thereby supporting transformation and tumorigenicity in vitro and in vivo. Clinically, high EIF4EBP1 expression is associated with poor outcomes in several cancer types. Our data reveal that the mTORC1-4EBP1/2 axis provokes a metabolic switch essential for survival during glucose starvation which is exploited by transformed and tumor cells.
AB - Energetic stress compels cells to evolve adaptive mechanisms to adjust their metabolism. Inhibition of mTOR kinase complex 1 (mTORC1) is essential for cell survival during glucose starvation. How mTORC1 controls cell viability during glucose starvation is not well understood. Here we show that the mTORC1 effectors eukaryotic initiation factor 4E binding proteins 1/2 (4EBP1/2) confer protection to mammalian cells and budding yeast under glucose starvation. Mechanistically, 4EBP1/2 promote NADPH homeostasis by preventing NADPH-consuming fatty acid synthesis via translational repression of Acetyl-CoA Carboxylase 1 (ACC1), thereby mitigating oxidative stress. This has important relevance for cancer, as oncogene-transformed cells and glioma cells exploit the 4EBP1/2 regulation of ACC1 expression and redox balance to combat energetic stress, thereby supporting transformation and tumorigenicity in vitro and in vivo. Clinically, high EIF4EBP1 expression is associated with poor outcomes in several cancer types. Our data reveal that the mTORC1-4EBP1/2 axis provokes a metabolic switch essential for survival during glucose starvation which is exploited by transformed and tumor cells.
UR - http://www.scopus.com/inward/record.url?scp=85193206153&partnerID=8YFLogxK
U2 - 10.1038/s41467-024-48386-y
DO - 10.1038/s41467-024-48386-y
M3 - Article
C2 - 38744825
AN - SCOPUS:85193206153
SN - 2041-1723
VL - 15
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 4083
ER -