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Oncogene (2005) 24, 30543058
& 2005 Nature Publishing Group All rights reserved 0950-9232/05 $30.00www.nature.com/oncBlockade of Wnt-1 signaling induces apoptosis in human colorectal cancer
cells containing downstream mutationsBiao He1, Noemi Reguart1,2, Liang You1, Julien Mazieres1,3, Zhidong Xu1, Amie Y Lee1, Iwao
Mikami1, Frank McCormick1 and David M Jablons*,11Thoracic Oncology Laboratory, Department of Surgery, Comprehensive Cancer Center, University of California, 1600 Divisadero St,
C322C, Box 1674, San Francisco, CA 94115, USA;2Medical Oncology Service, Institut Catala` dOncologia, Hospital Germans Trias
i Pujol, Badalona (Barcelona), Spain;3Department Innovation Therapeutique et Oncologie Moleculaire, INSERM U563, Institut
Claudius Regaud, 31052 Toulouse Cedex, FranceAberrant Wnt signaling, mainly through mutations of
APC and in some cases of CTNNB1 or AXIN2, has been
found in the majority of colorectal cancers. Recently,
frequent promoter hypermethylation was identied to
cause silencing of the secreted frizzled-related protein
(sFRP) family in colorectal cancer. Restoration of sFRP
in colorectal cancer cells attenuates Wnt signaling even in
the presence of downstream mutations. Here we show that
Wnt inhibitory factor-1 (WIF-1), a different secreted
antagonist of Wnt signaling, is also silenced by promoter
hypermethylation in colorectal cancer cells. Restoration of
WIF-1 function, Wnt-1 siRNA, or a monoclonal anti-
Wnt-1 antibody that we developed attenuates Wnt-1
signaling and induces signicant apoptosis in these cells
containing downstream mutations and expressing Wnt-1.
In addition, this monoclonal anti-Wnt-1 antibody showed
synergistic effects with docetaxel in treating these colorectal cancer cells and great efcacy in treating primary
colorectal cancer cultures freshly prepared from patients.
Therefore, our data support the hypothesis that constitutive Wnt signaling may be required to complement
downstream mutations in the evolution of colorectal
cancer. Furthermore, our results suggest that blockade
of the Wnt signal may have a therapeutic role in the
treatment of colorectal cancer.Oncogene (2005) 24, 30543058. doi:10.1038/sj.onc.1208511
Published online 14 February 2005Keywords: human; Wnt-1; colorectal cancer; apoptosisThe activation of the canonical pathway involves
activation of Dishevelled (Dvl), stabilization and accumulation of b-catenin in the nucleus, and activation of
b-catenin/T-cell factor (Tcf) complex to regulate transcription of downstream target genes for cell proliferation and differentiation (Giles et al., 2003; Taketo,
2004). In contrast, noncanonical signaling pathways do
not require b-catenin, and they signal through other
mediators, such as JNK, G proteins, or calcium ux
(Veeman et al., 2003). A number of Wnt antagonists