title: Kringle 5 of human plasminogen, an angiogenesis inhibitor, induces both autophagy and apoptotic death in endothelial cells.
abstract: Inhibition of endothelial cell proliferation and angiogenesis is emerging as an important strategy in cancer therapeutics. Kringle 5 (K5) of human plasminogen is a potent angiogenesis inhibitor. Previous studies have shown K5 exposure promotes caspase activity and apoptosis in endothelial cells. Here we report that K5 treatment evokes an autophagic response in endothelial cells that is specific and initiated even in the absence of nutritional stress. Endothelial cells exposed to K5 up-regulated Beclin 1 levels within a few hours. Furthermore, progressively increasing amounts of antiapoptotic Bcl-2 were found to be complexed with Beclin 1, although total levels of Bcl-2 remained unchanged. Prolonged exposure to K5 ultimately led to apoptosis via mitochondrial membrane depolarization and caspase activation in endothelial cells. Knocking down Beclin 1 levels by RNA interference decreased K5 induced autophagy but accelerated K5-induced apoptosis. These studies suggest that interfering with the autophagic survival response can potentiate the antiangiogenic effects of Kringle 5 in endothelial cells.
authors.affiliation: Department of Pharmacology, University of Minnesota Medical School, 321 Church Street SE, Minnesota, MN 55455, USA.
authors.forename: Tri Minh Bui
authors.initials: TM
authors.lastname: Nguyen
authors.forename: Indira V
authors.initials: IV
authors.lastname: Subramanian
authors.forename: Ameeta
authors.initials: A
authors.lastname: Kelekar
authors.forename: Sundaram
authors.initials: S
authors.lastname: Ramakrishnan
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis; D001343:Autophagy / Q000187:drug effects*; D000071186:Beclin-1; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D042783:Endothelial Cells / Q000166:cytology*; D004789:Enzyme Activation; D006801:Humans; D018082:Kringles; D008565:Membrane Proteins / Q000096:biosynthesis; D051336:Mitochondrial Membranes / Q000378:metabolism; D010958:Plasminogen / Q000737:chemistry* / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D020533:Angiogenesis Inhibitors; D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D008565:Membrane Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D010958:Plasminogen