Characterizing the functions and relevance of 4EBP1 in glioblastoma

• Applicant: Dr. Gabriel Leprivier
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Cell Biology
• Term: from 2017 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 379877200

• Final Report Year: 2021

Final Report Abstract

We investigated the role and clinical relevance of the stress response and translational regulator eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1) in glioblastoma to decipher how such brain tumors cope with metabolic stress. Using different 4EBP1 proficient and deficient cellular models of glioblastoma, we uncovered that 4EBP1 is contributing to glioblastoma tumorigenesis in vitro, as assessed by soft agar assays. This was validated in vivo by injecting the 4EBP1 glioblastoma models either in the flank or in the brain of mice. This clearly indicated that 4EBP1 is required for tumor xenografts formation in vivo. We next searched for the mechanisms underlying 4EBP1 pro-tumorigenic function. We found that 4EBP1 is critical to maintain the redox balance, which when disrupted prevents tumorigenesis. Metabolic analysis revealed that 4EBP1 is doing so by inhibiting fatty acid synthesis, a high consumer of the antioxidant cofactor NADPH. We characterized that 4EBP1 pro-tumorigenic function in vitro requires control of fatty acid synthesis. We dissected the molecular mechanisms involved and uncovered that 4EBP1, as a translational repressor, restricts the expression of the fatty acid synthesis enzyme Acetyl-CoA carboxylase 1 (ACC1). We demonstrated that in vivo the regulation of ACC1 by 4EBP1 is contributing to 4EBP1 function in promoting growth of glioblastoma tumor xenografts. Finally, we identified a 4EBP1 antibody for immunohistochemical staining and collected further evidence that EIF4EBP1 expression is a factor of poor prognosis in glioblastoma patients. Our work highlight that 4EBP1 is a pro-tumorigenic factor in glioblastoma and suggest that 4EBP1 may represent a therapeutic target to treat this disease. This research has been highlighted in public media, in die Welt (“Wie Tumorzellen ausgehungert werden“, Feb. 4th, 2020).

Publications

• Cystine/glutamate antiporter xCT (SLC7A11) facilitates oncogenic RAS transformation by preserving intracellular redox balance. Proc Natl Acad Sci U S A, 2019 May 7;116(19):9433-9442
  Lim JKM, Delaidelli A, Minaker SW, Zhang HF, Colovic M, Yang H, Negri GL, von Karstedt S, Lockwood WW, Schaffer P, Leprivier G, Sorensen PH
  
• High-Throughput Screening Identified Compounds Sensitizing Tumor Cells to Glucose Starvation in Culture and VEGF Inhibitors In Vivo. Cancers, 2019 Jan 30;11(2)
  Marciano R, Prasad M, Levy T, Tzadok S, Leprivier G, Elkabets M, Rotblat B
  
• 4EBP1/2 are active under standard cell culture conditions to regulate the translation of specific mRNAs. Cell Death Dis. 2020 Nov 11;11(11):968
  Alasad K, Voeltzke K, Levin L, Reifenberger G, Leprivier G, Rotblat B