Abstract
Vascular endothelial growth factor (VEGF) signaling pathway is essential for tumor angiogenesis and has long been recognized as a promising target for cancer therapy. Current view holds that physical interaction between αvβ3 integrin and kinase insert domain-containing receptor (KDR) is important in regulating angiogenesis and tumor development. We have reported previously that a new marine-derived compound, philinopside E (PE), exhibited the antiangiogenic activity via inhibition on KDR phosphorylation and downstream signaling. Herein, we have further demonstrated that PE specifically interacts with KDR extracellular domain, which is distinct from conventional small-molecule inhibitors targeting cytoplasmic kinase domain, to block its interaction with VEGF and the downstream signaling. We also noted that PE markedly suppresses αvβ3 integrin-driven downstream signaling as a result of disturbance of the physical interaction between KDR and αvβ3 integrin in HMECs, followed by disruption of the actin cytoskeleton organization and decreased cell adhesion to vitronectin. All of these findings substantiate PE to be an unrecognized therapeutic class in tumor angiogenesis and, more importantly, help appeal the interest of the therapeutic potential in angiogenesis and cancer development via targeting integrin-KDR interaction in the future.
Footnotes
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This work was supported by National Key Basic Research Project of China (grant 2004CB518903), National Natural Science Foundation (grant 30572201) and Knowledge Innovation Program of Chinese Academy of Sciences (grant KSCX2-YW-R-25).
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F.T. and C.Z. contributed equally to this work.
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Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
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doi:10.1124/mol.107.036350.
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ABBREVIATIONS: PE, philinopside E; KDR, kinase insert domain-containing receptor; HMEC, human dermal microvascular endothelial cell; VEGF, vascular endothelial growth factor; RTK, receptor tyrosine kinase; ELISA, enzyme-linked-immunosorbent assay; SPR, surface plasmon resonance assay; FBS, fetal bovine serum; ERK, extracellular signal-regulated kinase; DMSO, dimethyl sulfoxide; PBS, phosphate-buffered saline; OPD, o-phenylenediamine dihydrochloride.
- Received March 26, 2007.
- Accepted June 12, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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