Endostatin induces autophagy in endothelial cells by modulating Beclin 1 and beta-catenin levels

J Cell Mol Med. 2009 Sep;13(9B):3687-98. doi: 10.1111/j.1582-4934.2009.00722.x. Epub 2009 Feb 27.


Endostatin is a well-characterized endogenous inhibitor of angiogenesis that affects cell proliferation and migration by inhibiting integrin and Wnt-mediated signalling pathways. Here, we show that endothelial cells treated with native and P125A-endostatin activate autophagy. Because autophagy can either be protective or induce programmed cell death, experiments were carried out to understand the signalling pathways leading to autophagy in endothelial cells. P125A-endostatin treatment increased the levels of Beclin 1, a crucial molecule in vesicle nucleation and autophagy. The treatment also reduced the levels of Bcl-2, Bcl-x(L) and beta-catenin; however, progressively increasing amounts of Bcl-2 and Bcl-x(L) were found to be complexed with Beclin 1. Increased beta-catenin and Wnt-mediated signalling reduced Beclin 1 levels and rescued endothelial cells from endostatin-induced autophagy. Finally, knocking down Beclin 1 levels by RNA interference decreased autophagy and accelerated caspase activation in endostatin-treated cells. These studies suggest that endothelial cells may initiate autophagy as a survival response to limit the effects of angiogenesis inhibitors. Thus, interfering with autophagy can potentiate the effects of endostatin by promoting a switch to apoptosis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis Regulatory Proteins / metabolism*
  • Autophagy*
  • Beclin-1
  • Caspases / metabolism
  • Cell Line, Tumor
  • Endostatins / metabolism*
  • Endostatins / pharmacology
  • Endothelial Cells / cytology*
  • Enzyme Activation
  • Gene Expression Regulation*
  • Humans
  • Membrane Proteins / metabolism*
  • Phosphatidylinositol 3-Kinases / metabolism
  • RNA Interference
  • Time Factors
  • Umbilical Veins / cytology
  • beta Catenin / metabolism*


  • Apoptosis Regulatory Proteins
  • BECN1 protein, human
  • Beclin-1
  • Endostatins
  • Membrane Proteins
  • beta Catenin
  • Phosphatidylinositol 3-Kinases
  • Caspases