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Autophagy regulates transforming growth factor β signaling and receptor trafficking

Charles B Trelford1, Gianni M Di Guglielmo1

  • 1Schulich School of Medicine and Dentistry, Western University, Department of Physiology and Pharmacology, London, Ontario N6A 5B7, Canada.

Biochimica Et Biophysica Acta. Molecular Cell Research
|May 23, 2022
PubMed

Insights

Inhibiting autophagy reduces transforming growth factor beta (TGFβ) signaling, decreasing epithelial to mesenchymal transition (EMT) and cell migration in lung cancer. This occurs by regulating TGFβ receptor trafficking and Smad2/Smad3 phosphorylation.

Area of Science:

  • Cell Biology
  • Molecular Oncology
  • Cancer Research

Background:

  • Transforming growth factor beta (TGFβ) signaling promotes tumorigenesis via epithelial to mesenchymal transition (EMT) and cell migration.
  • TGFβ receptor endocytosis and trafficking regulate its signaling.
  • Autophagy, a cellular degradation process, plays a role in cellular signaling pathways.

Purpose of the Study:

  • To investigate the role of autophagy in regulating TGFβ-induced EMT and cell migration.
  • To determine how autophagy inhibition affects TGFβ receptor trafficking and downstream signaling.

Main Methods:

  • Autophagy was inhibited in non-small cell lung cancer cells using chemical inhibitors (chloroquine, spautin-1, ULK-101) and siRNA targeting ATG5 and ATG7.
  • TGFβ1-dependent EMT markers, cell migration, and stress fiber formation were assessed.
  • TGFβ receptor internalization and trafficking were analyzed.
  • Smad2/Smad3 phosphorylation and localization were evaluated using western blotting, subcellular fractionation, and immunofluorescence microscopy.

Main Results:

  • Autophagy inhibition decreased TGFβ1-induced EMT transcription factors, cell marker expression, stress fiber formation, and cell migration.
  • Inhibition of autophagy led to reduced internalization and lysosomal trafficking of TGFβ receptors.
  • Impaired autophagy attenuated Smad2/Smad3 phosphorylation and nuclear accumulation, shortening the signaling duration.

Conclusions:

  • Autophagy regulates TGFβ signaling pathways crucial for EMT and cell migration.
  • Inhibiting autophagy disrupts TGFβ receptor trafficking, thereby attenuating pro-tumorigenic TGFβ signaling.
  • Targeting autophagy may represent a therapeutic strategy to inhibit TGFβ-driven tumor progression.
Keywords:
AutophagyEpithelial to mesenchymal transition (EMT)Non-small cell lung cancer (NSCLC)Receptor-mediated endocytosisTransforming growth factor beta (TGFβ)

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