Inhibition of Wnt-2-mediated signaling induces programmed cell death in non-small-cell lung cancer cells.
In this report, we have demonstrated that Wnt-2 protein is overexpressed in freshly resected human non-small-cell lung cancer (NSCLC) tissues. We have also developed a monoclonal antibody against the N-terminus of human Wnt-2 protein. This monoclonal antibody induces apoptosis in human NSCLC cell lines that overexpress Wnt-2 protein. Incubation of this antibody with normal human airway cells lacking Wnt-2 expression does not induce apoptosis. Wnt-2 signaling blockade by the anti-Wnt-2 antibody is confirmed by downregulation of cytosolic beta-catenin and reduction in TCF-dependent transcriptional activity (TOPFLASH assay). In addition, Wnt-2-specific small interfering RNA (siRNA) treatment in the NSCLC cell line A549 also downregulated cytosolic beta-catenin and induced apoptosis. Moreover, downregulation of an inhibitor of apoptosis family protein, Survivin, was noticed both in the Wnt-2 antibody- and siRNA-treated NSCLC cells, suggesting that inhibition of Wnt-2-mediated signaling induces apoptosis through inactivating Survinin.
You
Liang
L
Thoracic Oncology Laboratory, Department of Surgery, Comprehensive Cancer Center, University of California, San Francisco, CA 94115, USA.
He
Biao
B
Xu
Zhidong
Z
Uematsu
Kazutsugu
K
Mazieres
Julien
J
Mikami
Iwao
I
Reguart
Noemi
N
Moody
Terry W
TW
Kitajewski
Jan
J
McCormick
Frank
F
Jablons
David M
DM
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D051154:Wnt2 Protein
D000911:Antibodies, Monoclonal; D011518:Proto-Oncogene Proteins; D051154:Wnt2 Protein