Article

Inhibition of Wnt-2 and galectin-3 synergistically destabilizes beta-catenin and induces apoptosis in human colorectal cancer cells.

Thoracic Oncology Laboratory, Department of Surgery, Comprehensive Cancer Center, University of California, San Francisco, CA 94115, USA.
International Journal of Cancer (Impact Factor: 5.01). 10/2007; 121(6):1175-81. DOI: 10.1002/ijc.22848
Source: PubMed

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 beta-catenin. In this study, we investigated roles of Wnt-2 and Gal-3 in the regulation of canonical Wnt/beta-catenin signaling. We found that siRNA silencing of either Wnt-2 or Gal-3 expression inhibited TCF-reporter activity, decreased cytosolic beta-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/beta-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.

0 Bookmarks
 · 
204 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Galectin-3, a member of β-galactoside-binding gene family is a multi-functional protein, which regulates pleiotropic biological functions such as cell growth, cell adhesion, cell- cell interactions, apoptosis, angiogenesis and mRNA processing. Its unique structure enables it to interact with a plethora of ligands in a carbohydrate dependent or independent manner. Galectin-3 is mainly a cytosolic protein, but can easily traverse the intracellular and plasma membranes to translocate into the nucleus, mitochondria or get externalized. Depending on the cell type, specific experimental conditions in vitro, cancer type and stage, galectin-3 has been reported to be exclusively cytoplasmic, predominantly nuclear or distributed between the two compartments. In this review we have summarized the dynamics of galectin-3 shuttling between the nucleus and the cytoplasm, the nuclear transport mechanisms of galectin-3, how its specific interactions with the members of β-catenin signaling pathways affect tumor progression, and its implications as a therapeutic target.
    Seminars in Cancer Biology 08/2014; · 9.14 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Galectin-3(Gal-3) plays important roles in cell proliferation, adhesion, differentiation, angiogenesis and apoptosis in normal and pathologic tissues. Accumulated evidences indicate Gal-3 is closely involved in tumor cell transformation, migration, invasion and metastasis. In this review, the associations of the expression and localization of Gal-3 as well as its potential action mechanism in tumorigenesis in a variety of cancers were summarized and concluded. Gal-3 is gaining its attraction as a potential new biomarker for the diagnosis, treatment and prognosis of certain tumors.
    Clinica chimica acta; international journal of clinical chemistry 02/2014; · 2.54 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Galectins are a family of animal lectins comprising 15 members in vertebrates. These proteins are involved in many biological processes including epithelial homeostasis and tumor progression by displaying intracellular and extracellular activities. Hence Galectins can be found either in the cytoplasm or the nucleus, associated with membranes or in the extracellular matrix. Current studies aim at understanding the roles of Galectins in cell-cell and cell-matrix adhesion, cellular polarity and motility. This review discusses recent progress in defining the specificities and mechanisms of action of Galectins as cell regulators in epithelial cells. Physiological, cellular and molecular aspects of Galectin specificities will be treated successively.
    Tissue barriers. 05/2014; 2:e29103.

Full-text (2 Sources)

Download
5 Downloads
Available from
Sep 20, 2014