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Inhibition of Wnt ‐2 and galectin‐3 synergistically destabilizes β‐catenin and induces apoptosis in human colorectal cancer cells
Author(s) -
Shi Yihui,
He Biao,
Kuchenbecker Kristopher M.,
You Liang,
Xu Zhidong,
Mikami Iwao,
YaguiBeltran Adam,
Clement Genevieve,
Lin YuChing,
Okamoto Junichi,
Bravo Dawn T.,
Jablons David M.
Publication year - 2007
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.22848
Subject(s) - wnt signaling pathway , colorectal cancer , cancer research , gene silencing , lrp5 , catenin , apoptosis , beta catenin , biology , lrp6 , signal transduction , chemistry , microbiology and biotechnology , cancer , genetics , gene
Abstract Constitutive activation of the Wnt pathway as a result of APC , AXIN1 or CTNNB1 mutations has been found in most colorectal cancers. For a long time, this aberrant Wnt activation has been thought to be independent of upstream signals. However, recent studies indicate that upstream signals retain their ability to regulate the Wnt pathway even in the presence of downstream mutations. Wnt‐2 is well known for its overexpression in colorectal cancer. Galectin‐3 (Gal‐3), a multifunctional carbohydrate binding protein implicated in a variety of biological functions, has recently been reported to interact with β‐catenin. In this study, we investigated roles of Wnt‐2 and Gal‐3 in the regulation of canonical Wnt/β‐catenin signaling. We found that siRNA silencing of either Wnt‐2 or Gal‐3 expression inhibited TCF‐reporter activity, decreased cytosolic β‐catenin level and induced apoptosis in human colorectal cancer cells containing downstream mutations. More interestingly, we showed that inhibition of both Wnt‐2 and Gal‐3 had synergistic effects on suppressing canonical Wnt signaling and inducing apoptosis, suggesting that aberrant canonical Wnt/β‐catenin signaling in colorectal cancer can be regulated at multiple levels. The combined inhibition of Wnt‐2 and Gal‐3 may be of superior therapeutic advantage to inhibition by either one of them, giving rise to a potential development of novel drugs for the targeted treatment of colorectal cancer. © 2007 Wiley‐Liss, Inc.