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mTORC1 regulates cell survival under glucose starvation through 4EBP1/2-mediated translational reprogramming of fatty

Tal Levy1,2, Kai Voeltzke3, Laura Hruby3

  • 1Department of Life Sciences, Faculty of Natural Sciences, Ben-Gurion University of the Negev, Beer-Sheva, 84105, Israel.

Nature Communications
|May 14, 2024
PubMed

Insights

The mTORC1-4EBP1/2 pathway protects cells from glucose starvation by maintaining NADPH levels. This survival mechanism is exploited by cancer cells, impacting tumor growth and patient outcomes.

Area of Science:

  • Cellular metabolism
  • Molecular oncology
  • Stress response

Background:

  • Cells adapt metabolism to energetic stress, with mTORC1 inhibition crucial for survival during glucose starvation.
  • The precise mechanisms by which mTORC1 regulates cell viability under these conditions remain unclear.

Purpose of the Study:

  • To elucidate the role of mTORC1 effectors, specifically 4EBP1/2, in cellular adaptation to glucose starvation.
  • To investigate the molecular mechanisms by which 4EBP1/2 confer protection.
  • To explore the implications of this pathway in cancer biology.

Main Methods:

  • Utilized mammalian cells and budding yeast models.
  • Investigated the impact of mTORC1 inhibition and 4EBP1/2 activity on cellular metabolism and redox balance.
  • Analyzed the translational regulation of Acetyl-CoA Carboxylase 1 (ACC1).
  • Examined the role of the mTORC1-4EBP1/2-ACC1 axis in cancer cell transformation and tumorigenicity in vitro and in vivo.

Main Results:

  • Demonstrated that eukaryotic initiation factor 4E binding proteins 1/2 (4EBP1/2) protect cells during glucose starvation.
  • Showed that 4EBP1/2 maintain NADPH homeostasis by repressing fatty acid synthesis through translational control of ACC1, thus mitigating oxidative stress.
  • Confirmed that cancer cells, including glioma cells, leverage this 4EBP1/2-mediated regulation of ACC1 and redox balance for survival and tumorigenesis.
  • Correlated high EIF4EBP1 expression with poor prognosis in multiple cancer types.

Conclusions:

  • The mTORC1-4EBP1/2 signaling axis induces a critical metabolic adaptation for survival under glucose starvation.
  • This adaptive pathway is co-opted by transformed and tumor cells, highlighting its significance in cancer progression.
  • Targeting the mTORC1-4EBP1/2 pathway may offer therapeutic strategies for cancers reliant on this metabolic adaptation.

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