Autophagy and angiogenesis inhibition.
Angiogenesis, the process by which new blood vessels are formed is critical for embryonic development and physiological functioning of normal tissues. Angiogenesis also plays a critical role in the pathology of many diseases including cancer, wherein the supply and demand for blood vessels determines the rate of cancer growth. A number of therapeutic strategies are being developed to inhibit pathological angiogenesis. Kringle domains of plasminogen such as kringle 5 (K5) and a proteolytic fragment of collagen type XVIII (endostatin) are well-characterized, potent angiogenesis inhibitors. These inhibitors activate different intracellular signaling pathways to induce apoptosis and inhibit cell proliferation. Recent studies from our group have shown that K5 and endostatin can also induce autophagy in addition to apoptosis in endothelial cells. A common feature of the two treatments was the upregulation of Beclin 1 levels leading to alterations in the Beclin 1-Bcl-2 complex. Angiogenesis inhibitor-induced autophagy in endothelial cells was independent of nutritional or hypoxic stress and initiated even in the presence of endothelial-specific survival factors such as vascular endothelial growth factor (VEGF). Interfering with the autophagic response by knocking down Beclin 1 levels dramatically increased apoptosis of endothelial cells. These findings identify the autophagic response as a novel target for enhancing the therapeutic efficacy of angiogenesis inhibitors.
Ramakrishnan
Sundaram
S
Department of Pharmacology, University of Minnesota, Minneapolis, Minnesota 55455, USA. sunda001@umn.edu
Nguyen
Tri Minh Bui
TM
Subramanian
Indira V
IV
Kelekar
Ameeta
A
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D051017:Apoptosis Regulatory Proteins / Q000502:physiology; D001343:Autophagy / Q000187:drug effects* / Q000502:physiology*; D000071186:Beclin-1; D043169:Endostatins / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology; D006801:Humans; D008565:Membrane Proteins / Q000502:physiology; D009389:Neovascularization, Pathologic; D010446:Peptide Fragments / Q000494:pharmacology; D010958:Plasminogen / Q000494:pharmacology; D015398:Signal Transduction
D020533:Angiogenesis Inhibitors; D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D043169:Endostatins; D008565:Membrane Proteins; D010446:Peptide Fragments; C491499:plasminogen kringle 5; D010958:Plasminogen