TIMP-2-derived 18-mer peptide inhibits endothelial cell proliferation and migration through cAMP/PKA-dependent mechanism

Cancer Lett. 2014 Feb 28;343(2):210-6. doi: 10.1016/j.canlet.2013.10.037. Epub 2013 Nov 16.


In the present study, we report the regulatory effects and molecular mechanisms of integrin α3β1-binding tissue inhibitor of metalloproteinases-2 (TIMP-2) 18-mer peptide (peptide 9) on proliferation, migration and tubular formation in human umbilical vein endothelial cells. Peptide 9 markedly inhibits vascular endothelial growth factor-A-stimulated cell proliferation. This anti-proliferative activity of peptide 9 is mediated by cAMP/protein kinase A (PKA)-dependent induction of p27(Kip1) expression as evidenced by using adenylate cyclase inhibitor SQ22536 or PKA inhibitor H89. Peptide 9-mediated inhibition of endothelial cell migration and tubular formation is also dependent on cAMP/PKA activity. Collectively, our findings clearly show the pharmacological roles and action mechanism of peptide 9 in regulating angiogenic responses through cAMP/PKA activity, and support further development as a potential therapeutics for the treatment of angiogenesis-related disorders including cancer.

Keywords: Angiogenesis; Integrin α3β1; Peptide 9; Protein kinase A; TIMP-2; cAMP.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Cyclic AMP / metabolism*
  • Cyclic AMP-Dependent Protein Kinases / metabolism*
  • Human Umbilical Vein Endothelial Cells / drug effects*
  • Humans
  • Peptides / genetics
  • Peptides / pharmacology*
  • Tissue Inhibitor of Metalloproteinase-2 / genetics
  • Tissue Inhibitor of Metalloproteinase-2 / pharmacology*


  • Antineoplastic Agents
  • Peptides
  • TIMP2 protein, human
  • Tissue Inhibitor of Metalloproteinase-2
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases