Antitumorigenic effects of a mutant of the heparin affin regulatory peptide on the U87 MG glioblastoma cell line.
Glioblastoma is the most common primary brain tumor in human adults. Since existing treatments are not effective enough, novel therapeutic targets must be sought. The heparin-binding growth factor, heparin affin regulatory peptide (HARP), also known as pleiotrophin (PTN), could potentially represent such a target. We have previously shown that a mutant protein, HARPDelta111-136, which lacks HARP's C-terminal 26 amino acids, acts as a dominant negative HARP effector by heterodimerizing with the wild-type growth factor. The aim of our study was to evaluate the potential inhibitory activity of HARPDelta111-136 on the U87 MG human glioblastoma cell line. By overexpressing the truncated form of HARP in stably established clones of U87 MG cells, we observed an inhibition of proliferation under both anchorage-dependent and anchorage-independent conditions. We confirmed these results in an in vivo subcutaneous tumor xenograft model. In addition, we found that HARPDelta111-136 inhibited cell proliferation in a paracrine manner. Analysis of key cellular pathways revealed a decrease of cell adhesion in U87 MG cells that overexpressed the mutant protein, which could explain this inhibitory effect. A replication-defective adenovirus model that encoded HARPDelta111-136 supported a putative antiproliferative role for the truncated protein in vitro and in vivo. Interestingly, HARPDelta111-136 was also able to abolish angiogenic activity in HUVEC proliferation and in a Matrigel plug assay. These results demonstrate that considering its antiproliferative and angiostatic effects, HARPDelta111-136 could be of great interest when used in conjunction with standard treatments.
Dos Santos
Célia
C
Laboratoire CRRET, EAC 7149 CNRS, Université Paris Est, Avenue du Général de Gaulle, 94010 Créteil Cedex, France.
Karaky
Racha
R
Renoir
Dominique
D
Hamma-Kourbali
Yamina
Y
Albanese
Patricia
P
Gobbo
Emilie
E
Griscelli
Frank
F
Opolon
Paule
P
Dalle
Sophie
S
Perricaudet
Michel
M
Courty
José
J
Delbé
Jean
J
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D016466:CHO Cells; D002352:Carrier Proteins / Q000235:genetics*; D002448:Cell Adhesion; D002465:Cell Movement; D049109:Cell Proliferation; D003094:Collagen / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D016207:Cytokines / Q000235:genetics*; D004338:Drug Combinations; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007124:Immunoenzyme Techniques; D007797:Laminin / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009154:Mutation / Q000235:genetics*; D010446:Peptide Fragments / Q000235:genetics / Q000494:pharmacology; D011509:Proteoglycans / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D002352:Carrier Proteins; D016207:Cytokines; D004338:Drug Combinations; D007797:Laminin; D010446:Peptide Fragments; D011509:Proteoglycans; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; C059485:matrigel; C066845:pleiotrophin; D003094:Collagen