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Canonical and Non-canonical TGFβ Signaling Activate Autophagy in an ULK1-Dependent Manner

Charles B Trelford1, Gianni M Di Guglielmo1

  • 1Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.

Frontiers in Cell and Developmental Biology
|November 11, 2021
PubMed

Insights

Transforming growth factor beta 1 (TGFβ) activates autophagy in lung cancer cells via Smad4 and TAK1-TRAF6-P38 MAPK pathways. These pathways are crucial for regulating autophagy, offering potential therapeutic targets for cancer treatment.

Area of Science:

  • Cell Biology
  • Molecular Oncology
  • Cancer Signaling

Background:

  • The role of transforming growth factor beta 1 (TGFβ) in modulating autophagy within cancer cells is not fully understood.
  • Autophagy is a cellular process implicated in cancer progression and treatment resistance.

Purpose of the Study:

  • To elucidate the specific TGFβ signaling pathways that induce autophagy in non-small cell lung cancer (NSCLC).
  • To identify key molecular players and their interactions in TGFβ-mediated autophagy.
  • To explore potential therapeutic targets for inhibiting TGFβ-driven autophagy in cancer.

Main Methods:

  • Utilized NSCLC cell lines engineered with GFP-LC3-RFP-LC3ΔG constructs to measure autophagic flux.
  • Investigated the impact of TGFβ1 on Unc 51-like kinase 1 (ULK1) phosphorylation and complex formation.
  • Employed siRNA-mediated silencing of Smad4 and inhibition of the TAK1-TRAF6-P38 MAPK pathway.

Main Results:

  • TGFβ1 increased ULK1 levels, AMPK-dependent ULK1 phosphorylation (S555), and ULK1 complex formation, while decreasing mTOR activity.
  • Both the canonical Smad4 pathway and the non-canonical TAK1-TRAF6-P38 MAPK pathway were essential for TGFβ1-induced autophagy.
  • The TAK1-TRAF6-P38 MAPK pathway was critical for downregulating mTOR (S2448) and ULK1 (S555) phosphorylation, impacting autophagosome formation.
  • Smad4 silencing reduced AMPK-dependent ULK1 phosphorylation (S555) and autophagosome formation.
  • Disruption of Smad4 or TAK1-TRAF6-P38 MAPK signaling impaired autophagosome-lysosome co-localization.

Conclusions:

  • The Smad4 and TAK1-TRAF6-P38 MAPK signaling pathways are indispensable for TGFβ-induced autophagy in NSCLC.
  • These pathways regulate key components of the autophagy machinery, including ULK1 and mTOR.
  • Targeting these specific TGFβ signaling pathways could offer a strategy to inhibit autophagy in cancer cells, particularly those undergoing epithelial-mesenchymal transition.
Keywords:
LC3BULK1autophagic fluxlung cancermTORmacroautophagytumorigenesis

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