Abstract
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 β-catenin; however, progressively increasing amounts of Bcl-2 and Bcl-x L were found to be complexed with Beclin 1. Increased β-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.
Original language | English (US) |
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Pages (from-to) | 3687-3698 |
Number of pages | 12 |
Journal | Journal of Cellular and Molecular Medicine |
Volume | 13 |
Issue number | 9 B |
DOIs | |
State | Published - Sep 2009 |
Keywords
- Angiogenesis
- Apoptosis
- Autophagy
- Bcl-2
- Bcl-xL
- Beclin 1
- Beta-catenin
- Endostatin
- Wnt-pathway