An anti-Wnt-2 monoclonal antibody induces apoptosis in malignant melanoma cells and inhibits tumor growth.
Activation of the Wnt/beta-catenin signaling pathway has been associated with human cancers. To test whether Wnt-2 signal is a survival factor in human melanoma cells and thus represents a potential therapeutic target, we investigated the effects of inhibition of Wnt-2 signaling in human melanoma cell lines. We have developed a novel monoclonal antibody against the NH(2) terminus of the human Wnt-2 ligand that induces apoptosis in human melanoma cells overexpressing Wnt-2. Whereas incubation of this antibody with normal cells lacking Wnt-2 expression does not induce apoptosis, Wnt-2 signaling blockade by the ligand-binding antibody is confirmed by down-regulation of Dishevelled and beta-catenin. Wnt-2 small interfering RNA treatment in these cells yielded similar apoptotic effects and downstream changes. Down-regulation of an inhibitor of apoptosis family protein, survivin, was observed in both the Wnt-2 antibody-treated and small interfering RNA-treated melanoma cell lines, suggesting that the antibody induces apoptosis by inactivating survivin. In an in vivo study, this monoclonal anti-Wnt-2 antibody suppresses tumor growth in a xenograft model. These findings suggest that the anti-Wnt-2 monoclonal antibody may be useful for the treatment of patients with malignant melanoma.
Thoracic Oncology Laboratory, Department of Surgery, Comprehensive Cancer Center, University of California-San Francisco, 1600 Divisadero Street, San Francisco, CA 94143-1674, USA.
Liang
L
You
Biao
B
He
Zhidong
Z
Xu
Kazutsugu
K
Uematsu
Julien
J
Mazieres
Naoaki
N
Fujii
Iwao
I
Mikami
Noemi
N
Reguart
Joe K
JK
McIntosh
Mohammed
M
Kashani-Sabet
Frank
F
McCormick
David M
DM
Jablons
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D017209:Apoptosis / Q000276:immunology*; D003598:Cytoskeletal Proteins / Q000378:metabolism; D000072261:Dishevelled Proteins; D015536:Down-Regulation; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008024:Ligands; D008545:Melanoma / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D009363:Neoplasm Proteins; D010750:Phosphoproteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D012878:Skin Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D000077022:Survivin; D015534:Trans-Activators / Q000378:metabolism; D051154:Wnt2 Protein; D014930:Women; D051176:beta Catenin
D048868:Adaptor Proteins, Signal Transducing; D000911:Antibodies, Monoclonal; C107489:BIRC5 protein, human; C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D000072261:Dishevelled Proteins; D051034:Inhibitor of Apoptosis Proteins; D008024:Ligands; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D000077022:Survivin; D015534:Trans-Activators; D051154:Wnt2 Protein; D051176:beta Catenin