Blockade of Wnt-1 signaling induces apoptosis in human colorectal cancer cells containing downstream mutations.
Aberrant 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 identified 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 significant 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 efficacy 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.
He
Biao
B
Thoracic Oncology Laboratory, Department of Surgery, Comprehensive Cancer Center, University of California, 1600 Divisadero St, C322C, Box 1674, San Francisco, CA 94115, USA.
Reguart
Noemi
N
You
Liang
L
Mazieres
Julien
J
Xu
Zhidong
Z
Lee
Amie Y
AY
Mikami
Iwao
I
McCormick
Frank
F
Jablons
David M
DM
D017209:Apoptosis / Q000502:physiology*; D015179:Colorectal Neoplasms / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D009154:Mutation; D051153:Wnt Proteins; D051155:Wnt1 Protein
D036341:Intercellular Signaling Peptides and Proteins; C495247:WNT1 protein, human; D051153:Wnt Proteins; D051155:Wnt1 Protein