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TAK1 activates AMPK-dependent cytoprotective autophagy in TRAIL-treated epithelial cells

Griselda Herrero-Martín1, Maria Høyer-Hansen, Celina García-García

  • 1Cell Signalling Department, Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), Consejo Superior de Investigaciones Científicas, Avenida Américo Vespucio s/n, Sevilla, Spain.

The EMBO Journal
|February 7, 2009
PubMed

Insights

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) activates protective autophagy in normal cells via AMP-activated protein kinase (AMPK). This novel pathway explains TRAIL resistance in healthy cells, crucial for cancer therapy development.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively induces apoptosis in cancer cells, making it a therapeutic target.
  • The mechanisms underlying differential TRAIL sensitivity between normal and cancer cells remain unclear.
  • Understanding these mechanisms is vital for developing effective TRAIL-based cancer therapies.

Purpose of the Study:

  • To elucidate the molecular mechanisms responsible for TRAIL resistance in normal cells.
  • To identify novel signaling pathways involved in cellular responses to TRAIL.
  • To explore the role of autophagy in TRAIL-mediated cytoprotection.

Main Methods:

  • Investigated TRAIL-induced signaling in untransformed human epithelial cells.
  • Utilized techniques to study autophagy activation and its mediators.
  • Examined the roles of AMP-activated protein kinase (AMPK), mammalian target of rapamycin complex 1 (mTORC1), and transforming growth factor-beta-activating kinase 1 (TAK1).

Main Results:

  • Identified a novel pathway where TRAIL activates cytoprotective autophagy in normal cells.
  • Demonstrated that TRAIL-induced autophagy is mediated by AMP-activated protein kinase (AMPK) inhibiting mTORC1.
  • Showed that TRAIL-induced AMPK activation is independent of LKB1 and CaMKKβ but dependent on TAK1 and TAB2.

Conclusions:

  • TRAIL triggers a protective autophagy response in normal cells through an AMPK-dependent pathway.
  • This pathway contributes to the resistance of untransformed cells against TRAIL-induced apoptosis.
  • Findings have broad implications for understanding energy homeostasis and cancer therapeutic resistance.

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