Decorin activates AMPK, an energy sensor kinase, to induce autophagy in endothelial cells.
The highly conserved eukaryotic process of macroautophagy (autophagy) is a non-specific bulk-degradation program critical for maintaining proper cellular homeostasis, and for clearing aged and damaged organelles. This decision is inextricably dependent upon prevailing metabolic demands and energy requirements of the cell. Soluble monomeric decorin functions as a natural tumor repressor that antagonizes a variety of receptor tyrosine kinases. Recently, we discovered that decorin induces endothelial cell autophagy, downstream of VEGFR2. This process was wholly dependent upon Peg3, a decorin-inducible genomically imprinted tumor suppressor gene. However, the signaling cascades responsible have remained elusive. In this report we discovered that Vps34, a class III phosphoinositide kinase, is an upstream kinase required for Peg3 induction. Moreover, decorin triggered differential formation of Vps34/Beclin 1 complexes with concomitant dissolution of inhibitive Bcl-2/Beclin 1 complexes. Further, decorin inhibited anti-autophagic signaling via suppression of Akt/mTOR/p70S6K activity with the concurrent activation of pro-autophagic AMPK-mediated signaling cascades. Mechanistically, AMPK is downstream of VEGFR2 and inhibition of AMPK signaling abrogated decorin-evoked autophagy. Collectively, these findings hint at the complexity of the underlying molecular relays necessary for decorin-evoked endothelial cell autophagy and reveal important therapeutic targets for augmenting autophagy and combatting tumor angiogenesis.
Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA; Cancer Cell Biology and Signaling Program, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Atul
A
Goyal
Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA; Cancer Cell Biology and Signaling Program, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Thomas
T
Neill
LifeCell Corporation, Branchburg, NJ 08876, USA.
Rick T
RT
Owens
Pharmazentrum Frankfurt, Goethe University, 60590 Frankfurt, Germany.
Liliana
L
Schaefer
Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA; Cancer Cell Biology and Signaling Program, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA. Electronic address: renato.iozzo@jefferson.edu.
Renato V
RV
Iozzo
D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy / Q000235:genetics*; D000071186:Beclin-1; D049109:Cell Proliferation / Q000235:genetics; D058546:Class III Phosphatidylinositol 3-Kinases / Q000378:metabolism; D058575:Decorin / Q000235:genetics / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism; D016147:Genes, Tumor Suppressor; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D058575:Decorin; D051741:Kruppel-Like Transcription Factors; D008565:Membrane Proteins; C490820:PEG3 protein, human; D058546:Class III Phosphatidylinositol 3-Kinases; C000588866:KDR protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2; D055372:AMP-Activated Protein Kinases
Decorin; IR-A; Proliferation; Signaling