Neuroblastoma angiogenesis is inhibited with a folded synthetic molecule corresponding to the epidermal growth factor-like module of the follistatin domain of SPARC

Alesandre Chlenski, Shuqing Liu, Lisa J. Baker, Qiwei Yang, Yufeng Tian, Helen R. Salwen, Susan L. Cohn

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

Secreted protein acidic and rich in cysteine (SPARC) is a multifunctional matricellular glycoprotein. In vitro, SPARC inhibits the proliferation and migration of endothelial cells stimulated by growth factors and induces endothelial cell apoptosis. We previously showed that SPARC also inhibits angiogenesis in vivo and impairs the growth of the pediatric tumor neuroblastoma (NB). SPARC comprises three domains that are independently folded by a complex pattern of disulfide bonds and have a high degree of structural conservation. In this study, separate modules of the SPARC domains were synthesized as cysteine-linked peptides and tested for their ability to inhibit angiogenesis. Peptide FS-E, representing the epidermal growth factor (EGF)-like module of the follistatin (FS) domain, did not cause endothelial cell apoptosis but strongly inhibited basic fibroblast growth factor (bFGF)-induced endothelial cell migration with an ED50 = 10 pmol/L. In vivo, peptide FS-E blocked bFGF-stimulated angiogenesis and neovascularization induced by NB cells. The EGF-like conformation was essential for peptide FS-E function because reduction of its two disulfide bonds completely abrogated peptide activity. Peptides FS-K and EC-N, corresponding to part of the Kazal module of the FS domain and the conserved α-helix in the extracellular calcium-binding domain, respectively, had minimal to no inhibitory activity. Our data show that the EGF-like module of the SPARC FS domain is angiosuppressive, and its structural conformation is critical for antiangiogenic activity.

Original languageEnglish (US)
Pages (from-to)7420-7425
Number of pages6
JournalCancer Research
Volume64
Issue number20
DOIs
StatePublished - Oct 15 2004

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Follistatin
Neuroblastoma
Epidermal Growth Factor
Cysteine
Endothelial Cells
Proteins
Fibroblast Growth Factor 2
Disulfides
Peptides
Apoptosis
Protein Domains
Cell Movement
Intercellular Signaling Peptides and Proteins
Glycoproteins
Pediatrics
Calcium
Growth

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Neuroblastoma angiogenesis is inhibited with a folded synthetic molecule corresponding to the epidermal growth factor-like module of the follistatin domain of SPARC. / Chlenski, Alesandre; Liu, Shuqing; Baker, Lisa J.; Yang, Qiwei; Tian, Yufeng; Salwen, Helen R.; Cohn, Susan L.

In: Cancer Research, Vol. 64, No. 20, 15.10.2004, p. 7420-7425.

Research output: Contribution to journalArticle

Chlenski, Alesandre ; Liu, Shuqing ; Baker, Lisa J. ; Yang, Qiwei ; Tian, Yufeng ; Salwen, Helen R. ; Cohn, Susan L. / Neuroblastoma angiogenesis is inhibited with a folded synthetic molecule corresponding to the epidermal growth factor-like module of the follistatin domain of SPARC. In: Cancer Research. 2004 ; Vol. 64, No. 20. pp. 7420-7425.
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