Endostatin induces autophagy in endothelial cells by modulating Beclin 1 and beta-catenin levels.
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.
Nguyen
Tri Minh Bui
TM
Department of Pharmacology, University of Minnesota, Minneapolis, MN 55455, USA.
Subramanian
Indira V
IV
Xiao
Xue
X
Ghosh
Goutam
G
Nguyen
Phan
P
Kelekar
Ameeta
A
Ramakrishnan
S
S
D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D001343:Autophagy; D000071186:Beclin-1; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D043169:Endostatins / Q000378:metabolism* / Q000494:pharmacology; D042783:Endothelial Cells / Q000166:cytology*; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D034622:RNA Interference; D013997:Time Factors; D014471:Umbilical Veins / Q000166:cytology; D051176:beta Catenin / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D043169:Endostatins; D008565:Membrane Proteins; D051176:beta Catenin; D019869:Phosphatidylinositol 3-Kinases; D020169:Caspases