Peptides derived from the histidine-proline domain of the histidine-proline-rich glycoprotein bind to tropomyosin and have antiangiogenic and antitumor activities.
The antiangiogenic activity of the multidomain plasma protein histidine-proline-rich glycoprotein (HPRG) is localized to its histidine-proline-rich (H/P) domain and has recently been shown to be mediated, at least partially, through binding to cell-surface tropomyosin in fibroblast growth factor-2-activated endothelial cells (X. Guan et al., Thromb Haemost, in press). HPRG and its H/P domain, but not the other domains of HPRG, bind specifically and with high affinity to tropomyosin. In this study, we characterize the interaction of the H/P domain with tropomyosin and delineate the region within the H/P domain responsible for that interaction. The H/P domain of HPRG consists mostly of repetitions of the consensus sequence [H/P][H/P]PHG. Applying an in vitro tropomyosin binding assay, we demonstrate that the synthetic peptide HHPHG binds to tropomyosin in vitro and inhibits angiogenesis and tumor growth in vivo. The affinity for tropomyosin increases exponentially upon multimerization of the HHPHG sequence, with a concurrent increase in antiangiogenic activity. Specifically, the tetramer (HHPHG)4 has significant antiangiogenic activity in the Matrigel plug model (IC50 approximately 600 nm) and antitumor effects in two syngeneic mouse tumor models. Thus, we show that a 16-mer peptide analogue mimics the antiangiogenic activity of intact HPRG and is also able to inhibit tumor growth, suggesting that cell surface tropomyosin may represent a novel antiangiogenic target for the treatment of cancer.
Doñate
Fernando
F
Attenuon, LLC, San Diego, California 92121, USA. donate@attunuon.com
Juarez
Jose C
JC
Guan
Xiaojun
X
Shipulina
Natalya V
NV
Plunkett
Marian L
ML
Tel-Tsur
Ziva
Z
Shaw
David E
DE
Morgan
William T
WT
Mazar
Andrew P
AP
D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy; D002645:Chickens; D004730:Endothelium, Vascular / Q000187:drug effects; D006801:Humans; D007700:Kinetics; D008546:Melanoma, Experimental / Q000188:drug therapy; D051379:Mice; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D014335:Tropomyosin / Q000378:metabolism*; D000099053:Histidine-Rich Glycoprotein
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D010446:Peptide Fragments; D011506:Proteins; D014335:Tropomyosin; D000099053:Histidine-Rich Glycoprotein