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Distinct roles for mammalian target of rapamycin complexes in the fibroblast response to transforming growth

Rod A Rahimi1, Mahefatiana Andrianifahanana, Mark C Wilkes

  • 1Department of Biochemistry and Molecular Biology, Thoracic Diseases Research Unit, Mayo Clinic Cancer Center, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA.

Cancer Research
|January 2, 2009
PubMed

Insights

Transforming growth factor-beta (TGF-beta) activates mTORC1 and mTORC2 in fibroblasts, driving fibrotic processes. Inhibiting mTOR may treat diseases like desmoplasia.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Oncology

Background:

  • Transforming growth factor-beta (TGF-beta) has diverse biological roles, including fibroblast proliferation.
  • TGF-beta signaling in epithelial cell growth inhibition is understood, but fibroblast responses are less clear.
  • Fibroblast-specific TGF-beta pathways are crucial for understanding fibrotic diseases and desmoplasia.

Purpose of the Study:

  • Investigate the role of mammalian target of rapamycin (mTOR) in fibroblast response to TGF-beta.
  • Determine the specific roles of mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) in TGF-beta signaling.

Main Methods:

  • Utilized fibroblasts and epithelial cells.
  • Examined TGF-beta-induced activation of mTORC1 and mTORC2.
  • Assessed the effects of rapamycin (mTOR inhibitor) on TGF-beta-mediated cellular responses.
  • Investigated Akt phosphorylation at S473.

Main Results:

  • TGF-beta activates mTORC1 in fibroblasts via a PI3K-Akt-TSC2 pathway, but not in epithelial cells.
  • Rapamycin blocked TGF-beta-induced anchorage-independent growth but not transcriptional changes or ECM production.
  • mTORC2 mediates TGF-beta-induced morphologic changes and Akt S473 phosphorylation.
  • Both mTORC1 and mTORC2 are essential for TGF-beta-induced soft agar growth.

Conclusions:

  • mTORC1 and mTORC2 have distinct yet overlapping roles in fibroblast response to TGF-beta.
  • mTOR signaling is critical for TGF-beta-driven fibroblast proliferation and fibrotic processes.
  • mTOR inhibitors show potential for treating fibrotic conditions like desmoplasia.

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