Striking the target in Wnt-y conditions: intervening in Wnt signaling during cancer progression

Abstract

Wnt signaling can be divided into three pathways, namely the canonical Wnt/beta-catenin pathway, and the non-canonical (or heretical) Wnt/Ca(2+) and planar cell polarity (PCP) pathways. Although the canonical Wnt/beta-catenin pathway is the best described in cancer, increasing data points to the importance of the heretical Wnt pathways in several aspects of tumor progression. The recent advances in understanding the players and mechanisms by which these Wnt pathways contribute to cancer progression have led to the identification of numerous molecules that are already, or could be considered, targets for cancer therapy.

Figure 1. The Wnt/β-Catenin Signaling Pathway and Points of Intervention

Receptor activation upon binding of Wnt 1 or Wnt3A leads to stabilization of β-catenin which localizes to the nucleus where it associates with transcription factors and activates transcription of genes involved in proliferation and tumor progression. In the absence of Wnt, transcription of these genes is prevented by phosphorylation of β-catenin by GSK3β within a destruction complex and its subsequent degradation via the proteasome.

Figure 2. The Wnt/PCP Signaling Pathway and Points of Intervention

Receptor activation by Wnt leads to the recruitment of Dsv, resulting in the activation of Rac1 and RhoA, both of which are involved in cytoskeletton remodeling and establishment of an EMT phenotype.

Figure 3. The Wnt/Ca2+ Signaling Pathway and Points of Intervention

Binding of Wnt5A to ROR2 leads to the activation of Ca2+ and PKC, which in turn stabilizes Wnt5A mRNA and increases its secretion. Secreted Wnt5A is presented to the receptor by HSPGs, resulting in a positive feedback loop. The Wnt5A-mediated increase in Ca2+ resluts in an increase in calpain-dependent filamin cleavage as well as activation of calcineurin and NFAT. Increases in PKC are associated with changes in the expression of proteins involved in the promotion of a metastatic phenotype including the upregulation of CD44 and SNAIL, loss of KISS1 and ECAD and establishment of an EMT. Increases in PKC are also associated with an increase in phospho-STAT3, which in melanoma leads to a decrease in melanosomal antigens.