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

EMBO J. 2009 Mar 18;28(6):677-85. doi: 10.1038/emboj.2009.8. Epub 2009 Feb 5.

Abstract

The capacity of tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) to trigger apoptosis preferentially in cancer cells, although sparing normal cells, has motivated clinical development of TRAIL receptor agonists as anti-cancer therapeutics. The molecular mechanisms responsible for the differential TRAIL sensitivity of normal and cancer cells are, however, poorly understood. Here, we show a novel signalling pathway that activates cytoprotective autophagy in untransformed human epithelial cells treated with TRAIL. TRAIL-induced autophagy is mediated by the AMP-activated protein kinase (AMPK) that inhibits mammalian target of rapamycin complex 1, a potent inhibitor of autophagy. Interestingly, the TRAIL-induced AMPK activation is refractory to the depletion of the two known AMPK-activating kinases, LKB1 and Ca(2+)/calmodulin-dependent kinase kinase-beta, but depends on transforming growth factor-beta-activating kinase 1 (TAK1) and TAK1-binding subunit 2. As TAK1 and AMPK are ubiquitously expressed kinases activated by numerous cytokines and developmental cues, these data are most likely to have broad implications for our understanding of cellular control of energy homoeostasis as well as the resistance of untransformed cells against TRAIL-induced apoptosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / metabolism*
  • Animals
  • Autophagy / drug effects*
  • Breast / cytology
  • Calcium-Calmodulin-Dependent Protein Kinase Kinase / metabolism
  • Cytoprotection / drug effects*
  • Enzyme Activation / drug effects
  • Epithelial Cells / cytology*
  • Epithelial Cells / drug effects
  • Epithelial Cells / enzymology*
  • Humans
  • Interleukin-1beta / pharmacology
  • MAP Kinase Kinase Kinases / metabolism*
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Models, Biological
  • Multiprotein Complexes
  • Protein-Serine-Threonine Kinases / metabolism
  • Proteins
  • Retinal Pigment Epithelium / cytology
  • TNF-Related Apoptosis-Inducing Ligand / pharmacology*
  • TOR Serine-Threonine Kinases
  • Transcription Factors / antagonists & inhibitors

Substances

  • Interleukin-1beta
  • Multiprotein Complexes
  • Proteins
  • TNF-Related Apoptosis-Inducing Ligand
  • Transcription Factors
  • STK11 protein, human
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • PRKAA1 protein, human
  • Protein-Serine-Threonine Kinases
  • Calcium-Calmodulin-Dependent Protein Kinase Kinase
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7
  • AMP-Activated Protein Kinases