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.