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CLT1 targets angiogenic endothelium through CLIC1 and fibronectin

Lynn M Knowles1, Gunjan Malik, Brian L Hood

  • 1Department of Urology, University of Pittsburgh School of Medicine, Shadyside Medical Center, Suite G33, 5200 Centre Avenue, Pittsburgh, PA 15232, USA.

Angiogenesis
|December 29, 2011
PubMed

Insights

CLT1 peptide targets tumor blood vessel growth by forming aggregates with fibronectin. This process induces cell death in endothelial cells, inhibiting tumor growth and metastasis.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • Angiogenesis is crucial for tumor progression and metastasis.
  • CLT1 peptide shares structural similarities with known anti-angiogenic peptides.
  • Tumor interstitial spaces contain fibrin-fibronectin, where CLT1 binds.

Purpose of the Study:

  • To investigate the anti-angiogenic potential and mechanism of action of the peptide CLT1.
  • To elucidate the role of Chloride Intracellular Channel 1 (CLIC1) in CLT1's activity.
  • To evaluate CLT1's efficacy in inhibiting angiogenesis and tumor growth in vivo.

Main Methods:

  • Investigated CLT1's interaction with fibronectin and its effect on endothelial cells in vitro.
  • Assessed CLT1-induced cytotoxicity, unfolded protein response, and autophagic cell death.
  • Examined the role of the LIIQK sequence and CLIC1 in CLT1 internalization and activity.
  • Validated findings in vivo by assessing CLT1 co-localization, angiogenesis inhibition, and tumor growth reduction.

Main Results:

  • CLT1 forms co-aggregates with fibronectin, inducing an unfolded protein response and autophagic cell death in endothelial cells.
  • CLIC1 mediates CLT1-fibronectin co-aggregate internalization via integrin αvβ3, dependent on CLT1's LIIQK sequence.
  • CLT1 treatment demonstrated significant inhibition of angiogenesis and tumor growth in vivo.
  • CLT1 co-localized with CLIC1 and fibronectin in tumor angiogenic blood vessels.

Conclusions:

  • CLT1 is a novel anti-angiogenic compound with a potent mechanism of action.
  • CLT1's mechanism involves fibronectin co-aggregation, CLIC1-mediated internalization, and induction of cytotoxic unfolded protein response.
  • CLT1's simple structure and high efficacy suggest its potential for anti-angiogenic therapies.

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