CLT1 targets angiogenic endothelium through CLIC1 and fibronectin.

Abstract

Angiogenesis is important for tumor growth and metastasis. CLT1 (CGLIIQKNEC), a peptide that binds to tumor interstitial spaces in the presence of fibrin-fibronectin, has structural similarity to the anti-angiogenic β-sheet peptides anastellin and anginex. This similarity is reflected in the ability of CLT1 to form co-aggregates with fibronectin that induce an unfolded protein response and cause autophagic cell death in proliferating endothelial cells. CLT1 cytotoxicity is mediated at least in parts by a novel CLT1 binding protein, Chloride Intracellular Channel 1 (CLIC1), which promotes internalization of CLT1-fibronectin co-aggregates in a mechanism that depends on the LIIQK amino acid sequence of CLT1. LIIQK encompasses amino acid residues relevant for CLT1 binding to CLIC1 and in addition, facilitates the formation of CLT1-fibronectin co-aggregates, which in turn promote translocation of CLIC1 to the endothelial cell surface through ligation of integrin αvβ3. Paralleling the in vitro results, we found that CLT1 co-localizes with CLIC1 and fibronectin in angiogenic blood vessels in vivo, and that CLT1 treatment inhibited angiogenesis and tumor growth. Our findings show that CLT1 is a new anti-angiogenic compound, and its mechanism of action is to form co-aggregates with fibronectin, which bind to angiogenic endothelial cells through integrins, become internalized through CLIC1 and elicit a cytotoxic unfolded protein response. The simple structure and high potency of CLT1 make it a potentially useful compound for anti-angiogenic treatments.

• Authors: Lynn M Knowles, Gunjan Malik, Brian L Hood, Thomas P Conrads, Jan Pilch
• Journal: Angiogenesis (Angiogenesis) Vol. 15 Issue 1 Pg. 115-29 (Mar 2012) ISSN: 1573-7209 [Electronic] Germany
• PMID: 22203240 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Angiogenesis Inhibitors
• Antineoplastic Agents
• CLIC1 protein, human
• Chloride Channels
• Fibronectins
• Peptides, Cyclic
• cyclo(cysteinyl-glycyl-leucyl-isoleucyl-isoleucyl-glutaminyl-lysyl-asparaginyl-glutamyl-cysteinyl)

Topics

• Amino Acid Sequence
• Angiogenesis Inhibitors (chemistry, pharmacology, therapeutic use)
• Animals
• Antineoplastic Agents (chemistry, pharmacology, therapeutic use)
• Cell Death (drug effects)
• Cell Line, Tumor
• Cell Membrane (drug effects, metabolism)
• Cell Proliferation (drug effects)
• Chloride Channels (metabolism)
• Endocytosis (drug effects)
• Endothelium, Vascular (drug effects, metabolism)
• Fibronectins (chemistry, metabolism)
• Human Umbilical Vein Endothelial Cells (cytology, drug effects, metabolism)
• Humans
• Lysosomes (drug effects, metabolism)
• Male
• Mice
• Mice, Nude
• Molecular Sequence Data
• Neovascularization, Pathologic (drug therapy, pathology)
• Neovascularization, Physiologic (drug effects)
• Peptides, Cyclic (chemistry, pharmacology, therapeutic use)
• Protein Structure, Quaternary