title: Angiostatin regulates the expression of antiangiogenic and proapoptotic pathways via targeted inhibition of mitochondrial proteins.
abstract: Angiostatin, a proteolytic fragment of plasminogen, is a potent endogenous antiangiogenic agent. The molecular mechanisms governing angiostatin's antiangiogenic and antitumor effects are not well understood. Here, we report the identification of mitochondrial compartment as the ultimate target of angiostatin. After internalization of angiostatin into the cell, at least 2 proteins within the mitochondria bind this molecule: malate dehydrogenase, a member of Krebs cycle, and adenosine triphosphate synthase. In vitro and in vivo studies revealed differential regulation of key prosurvival and angiogenesis-related proteins in angiostatin-treated tumors and tumor-endothelium. Angiostatin induced apoptosis via down-regulation of mitochondrial BCL-2. Angiostatin treatment led to down-regulation of c-Myc and elevated levels of another key antiangiogenic protein, thrombospondin-1, reinforcing its antitumor and antiangiogenic effects. Further evidence is provided for reduced recruitment and infiltration of bone marrow-derived macrophages in angiostatin-treated tumors. The observed effects of angiostatin were restricted to the tumor site and were not observed in other major organs of the mice, indicating unique tumor specific bioavailability. Together, our data suggest mitochondria as a novel target for antiangiogenic therapy and provide mechanistic insights to the antiangiogenic and antitumor effects of angiostatin.
authors.affiliation: Department of Surgery, Children's Hospital Boston and Harvard Medical School, MA, USA.
authors.forename: Tong-Young
authors.initials: TY
authors.lastname: Lee
authors.forename: Stefan
authors.initials: S
authors.lastname: Muschal
authors.forename: Elke A
authors.initials: EA
authors.lastname: Pravda
authors.forename: Judah
authors.initials: J
authors.lastname: Folkman
authors.forename: Amir
authors.initials: A
authors.lastname: Abdollahi
authors.forename: Kashi
authors.initials: K
authors.lastname: Javaherian
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D043168:Angiostatins / Q000502:physiology*; D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008928:Mitochondria / Q000378:metabolism*; D008954:Models, Biological; D009369:Neoplasms / Q000628:therapy; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D043168:Angiostatins