A prostate secretory protein94-derived synthetic peptide PCK3145 inhibits VEGF signalling in endothelial cells: implication in tumor angiogenesis.
We have previously observed that the synthetic peptide corresponding to amino acids 31-45 (PCK3145) of PSP94 can reduce prostate tumor growth in vivo. Moreover, a recently concluded phase IIa clinical trial with patients with hormone refractory prostate cancer indicated that PCK3145 down-regulates the levels of plasma matrix metalloproteinase (MMP)-9, a MMP involved in metastasis and tumor angiogenesis. The purpose of our study was to investigate the molecular mechanisms of action of PCK3145 and whether this peptide could antagonize tumor neovascularization. We show that, in a syngeneic in vivo model of rat prostate cancer, the expression of endothelial cell (EC) specific CD31, a marker of tumor vessel density, was decreased by 43% in PCK3145-treated animals. In vitro, PCK3145 specifically antagonized in a dose-dependent manner the VEGF-induced ERK phosphorylation as well as the phosphorylation of the VEGFR-2 in cultured EC (HUVEC). These anti-VEGF effects were partly reproduced by pharmacological inhibitors such as PD98059 and PTK787, suggesting that PCK3145 inhibits the tyrosine kinase activity associated to VEGFR-2, which in turn prevents intracellular signalling through the MAPK cascade. Moreover, PCK3145 was also found to inhibit the PDGF-induced phosphorylation of PDGFR in smooth muscle cells. Finally, PCK3145 inhibited in vitro EC tubulogenesis and VEGF-induced MMP-2 secretion suggesting its potential implication as an antiangiogenic agent. Our study demonstrates that PCK3145 interferes with the tyrosine kinase activity associated with VEGF signalling axis in EC. The antiangiogenic properties of this peptide could be highly beneficial and exploited in novel antiangiogenic therapies, for patients with various cancers.
Lamy
Sylvie
S
Centre de Cancérologie Charles-Bruneau, Hôpital Sainte-Justine-UQAM, Montreal, Quebec, Canada.
Ruiz
Marcia T
MT
Wisniewski
Jan
J
Garde
Seema
S
Rabbani
Shafaat A
SA
Panchal
Chandra
C
Wu
Jinzi J
JJ
Annabi
Borhane
B
D000818:Animals; D018929:Cell Culture Techniques; D042783:Endothelial Cells; D008297:Male; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009130:Muscle, Smooth; D009389:Neovascularization, Pathologic / Q000503:physiopathology*; D010446:Peptide Fragments / Q000494:pharmacology*; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000098:blood supply* / Q000188:drug therapy; D029584:Prostatic Secretory Proteins; D051381:Rats; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000187:drug effects* / Q000502:physiology*
D010446:Peptide Fragments; D029584:Prostatic Secretory Proteins; D042461:Vascular Endothelial Growth Factor A; C506581:tigapotide; D020929:Mitogen-Activated Protein Kinase Kinases