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

Tri Minh Bui Nguyen1, Indira V Subramanian, Xue Xiao

  • 1Department of Pharmacology, University of Minnesota, Minneapolis, MN 55455, USA.

Journal of Cellular and Molecular Medicine
|March 21, 2009
PubMed

Insights

Endostatin, an angiogenesis inhibitor, triggers autophagy in endothelial cells. Inhibiting autophagy enhances endostatin

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • Endostatin is a known endogenous inhibitor of angiogenesis, impacting cell proliferation and migration.
  • It functions by inhibiting integrin and Wnt-mediated signaling pathways.
  • The role of autophagy, a cellular degradation process, in response to endostatin is not fully understood.

Purpose of the Study:

  • To investigate the signaling pathways involved in autophagy activation in endothelial cells treated with endostatin.
  • To determine the role of autophagy as a survival or death mechanism in response to endostatin.
  • To explore the potential of modulating autophagy to enhance anti-angiogenic therapies.

Main Methods:

  • Treatment of endothelial cells with native and P125A-mutant endostatin.
  • Analysis of autophagy-related proteins (Beclin 1, Bcl-2, Bcl-x(L)) and beta-catenin levels.
  • Assessment of protein complex formation using co-immunoprecipitation.
  • RNA interference (RNAi) to knock down Beclin 1 expression.
  • Measurement of caspase activation to indicate apoptosis.

Main Results:

  • Endostatin treatment induced autophagy in endothelial cells, evidenced by increased Beclin 1 levels.
  • Endostatin reduced Bcl-2, Bcl-x(L), and beta-catenin, with Bcl-2 and Bcl-x(L) forming complexes with Beclin 1.
  • Restoration of beta-catenin and Wnt signaling inhibited autophagy and protected cells.
  • Beclin 1 knockdown accelerated caspase activation, indicating apoptosis.

Conclusions:

  • Endothelial cells activate autophagy as a survival response to endostatin-induced anti-angiogenic stress.
  • The Beclin 1-Bcl-2/Bcl-x(L) interaction is critical in mediating endostatin-induced autophagy.
  • Interfering with autophagy can potentiate endostatin's anti-cancer effects by promoting apoptosis.

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