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The mTORC1/S6K1 pathway regulates glutamine metabolism through the eIF4B-dependent control of c-Myc translation

Alfredo Csibi1, Gina Lee1, Sang-Oh Yoon1

  • 1Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA.

Current Biology : CB
|September 16, 2014
PubMed

Insights

Mammalian target of rapamycin complex 1 (mTORC1) promotes cancer growth by increasing glutaminase (GLS) levels via S6K1 and c-Myc. Inhibiting GLS shows promise for treating PTEN-low pancreatic cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Metabolism

Background:

  • Cancer cells reprogram metabolism to support rapid growth and proliferation, often driven by signaling molecules like mTORC1.
  • Glutamine fuels the tricarboxylic acid (TCA) cycle via glutaminase (GLS) and glutamate dehydrogenase (GDH).
  • mTORC1 activation promotes glutamine anaplerosis via GDH and stimulates glutamine uptake, but the underlying mechanism for GLS regulation is unclear.

Purpose of the Study:

  • To investigate the mechanism by which mTORC1 regulates glutamine metabolism, specifically focusing on glutaminase (GLS).
  • To elucidate the role of S6K1 and c-Myc in mTORC1-mediated GLS regulation.
  • To evaluate the therapeutic potential of GLS inhibition in pancreatic cancer.

Main Methods:

  • Investigated mTORC1 regulation of GLS and glutamine flux in cancer cells.
  • Utilized S6K1 and c-Myc signaling pathways to understand GLS control.
  • Examined the effect of eukaryotic initiation factor eIF4B phosphorylation on c-Myc translation.
  • Assessed the efficacy of pharmacological GLS inhibition in PTEN-low pancreatic cancer models.

Main Results:

  • Demonstrated that mTORC1 positively regulates GLS expression and activity, increasing glutamine flux.
  • Showed that mTORC1 controls GLS levels through S6K1-dependent regulation of c-Myc.
  • Identified that S6K1 enhances c-Myc translation efficiency by modulating eIF4B phosphorylation.
  • Found that pharmacological inhibition of GLS is effective in pancreatic cancers with low PTEN expression.

Conclusions:

  • mTORC1 signaling is a key regulator of glutaminase (GLS) in cancer, controlling glutamine metabolism and supporting cancer cell proliferation.
  • The S6K1-c-Myc-eIF4B axis mediates mTORC1's control over GLS levels.
  • Targeting GLS represents a promising therapeutic strategy for specific subsets of pancreatic cancer, particularly those with low PTEN.

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