Journal Article

DKFZ-2024-01032

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png mTORC1 regulates cell survival under glucose starvation through 4EBP1/2-mediated translational reprogramming of fatty acid metabolism.

Levy, T. ; Voeltzke, K. ; Hruby, L. ; Alasad, K. ; Bas, Z. ; Snaebjörnsson, M. T.DKFZ* ; Marciano, R. ; Scharov, K. ; Planque, M. ; Vriens, K. ; Christen, S. ; Funk, C.DKFZ* ; Hassiepen, C. ; Kahler, A. ; Heider, B. ; Picard, D. J.DKFZ* ; Lim, J. K. M. ; Stefanski, A. ; Bendrin, K. ; Vargas-Toscano, A. ; Kahlert, U. D. ; Stühler, K. ; Remke, M.DKFZ* ; Elkabets, M. ; Grünewald, T.DKFZ* ; Reichert, A. S. ; Fendt, S.-M. ; Schulze, A.DKFZ* ; Reifenberger, G.DKFZ* ; Rotblat, B. ; Leprivier, G.

2024
Nature Publishing Group UK [London]

This record in other databases:  

Please use a persistent id in citations: doi:10.1038/s41467-024-48386-y

Abstract: 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.

Keyword(s): Mechanistic Target of Rapamycin Complex 1: metabolism (MeSH) ; Mechanistic Target of Rapamycin Complex 1: genetics (MeSH) ; Glucose: metabolism (MeSH) ; Acetyl-CoA Carboxylase: metabolism (MeSH) ; Acetyl-CoA Carboxylase: genetics (MeSH) ; Humans (MeSH) ; Adaptor Proteins, Signal Transducing: metabolism (MeSH) ; Adaptor Proteins, Signal Transducing: genetics (MeSH) ; Fatty Acids: metabolism (MeSH) ; Animals (MeSH) ; Cell Survival (MeSH) ; Cell Cycle Proteins: metabolism (MeSH) ; Cell Cycle Proteins: genetics (MeSH) ; Mice (MeSH) ; NADP: metabolism (MeSH) ; Protein Biosynthesis (MeSH) ; Phosphoproteins: metabolism (MeSH) ; Phosphoproteins: genetics (MeSH) ; Oxidative Stress (MeSH) ; Cell Line, Tumor (MeSH) ; Eukaryotic Initiation Factors: metabolism (MeSH) ; Eukaryotic Initiation Factors: genetics (MeSH)

---

Contributing Institute(s):

1. Metabolismus und Microenvironment (A410)
2. Translationale Pädiatrische Sarkomforschung (B410)
3. DKTK HD zentral (HD01)
4. DKTK Koordinierungsstelle Essen/Düsseldorf (ED01)

Research Program(s):

1. 311 - Zellbiologie und Tumorbiologie (POF4-311) (POF4-311)

Appears in the scientific report 2024

---

Database coverage:
; ; ; Article Processing Charges ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Agriculture, Biology and Environmental Sciences ; Current Contents - Life Sciences ; Current Contents - Physical, Chemical and Earth Sciences ; DOAJ Seal ; Essential Science Indicators ; Fees ; IF >= 15 ; JCR ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection ; Zoological Record

---