Targeting the Wnt pathways for therapies

Abstract

The Wnt/β-catenin signaling pathway is crucial in animal development from sponges to humans. Its activity in the adulthood is less general, with exceptions having huge medical importance. Namely, improper activation of this pathway is carcinogenic in many tissues, most notably in the colon, liver and the breast. On the other hand, the Wnt/β-catenin signaling must be re-activated in cases of tissue damage, and insufficient activation results in regeneration failure and degeneration. These both medically important implications are unified by the emerging importance of this signaling pathway in the control of proliferation of various types of stem cells, crucial for tissue regeneration and, in case of cancer stem cells – cancer progression and relapse. This article aims at briefly reviewing the current state of knowledge in the field of Wnt signaling, followed by a detailed discussion of current medical developments targeting distinct branches of the Wnt pathway for anti-cancer and pro-regeneration therapies.

Targeting the WNT Signaling Pathway in Cancer Therapeutics

“…LGK974 demonstrated antitumor response in in vivo breast, pancreas, and head and neck cancers [27]. Intriguingly, all LGK974-sensitive pancreatic cell lines carried a loss-of-function mutation in the ubiquitin E3 ligase ring finger 43 (RNF43) gene.…”

Forced expression of Wnt antagonists sFRP1 and WIF1 sensitizes chronic myeloid leukemia cells to tyrosine kinase inhibitors

“…Silencing of these genes via hypermethylation of their promoters has been shown to be part of the pathogenesis in a plethora of human malignancies. [1][2][3][4][5][6] Aberrant regulation of the Wnt signaling pathway is known to play a role in tumorigenesis and maintenance of cancer stem cells. 3,4,28 The Wnt pathway can be activated aberrantly not only by mutations of genes functioning in Wnt signaling such as APC and CTNNB1 but also by dysregulation of secreted antagonists.…”

“…Therefore, mechanisms that may inhibit the abnormal functioning of the pathway are of therapeutic interest. 6 Adenomatous Polyposis Coli (APC) and β-catenin mutations, as well as altered expression of the pathway components represent important mechanisms underlying abnormal activation of Wnt/β-catenin signaling. 9 Deregulated activation of the canonical Wnt pathway is also observed in leukemia.…”

“…[1][2][3][4][5][6] Wnt/β-catenin signaling has pivotal roles both in early developmental stages and in tissue maintenance of adults. The pathway operates by regulating specific genes that function in cell fate, proliferation, polarity, migration, and differentiation.…”

6BIO Enhances Oligonucleotide Activity in Cells: A Potential Combinatorial Anti-androgen Receptor Therapy in Prostate Cancer Cells

“…16,37,38 The effects of the combination of 6BIO and the ASO on the targeting on b-catenin were of particular interest in view of the potential capability of 6BIO to activate the Wnt/b-catenin pathway 39 through the suppression of glycogen synthase kinase (GSK)-3b, a b-catenin inhibitor. 39 Nevertheless, the treatment of LNCaP cells with 6BIO and a b-catenin ASO (b-Cat-ASO+ 6BIO) still decreased the b-catenin mRNA expression by approximately 90% compared with a 65% reduction with ASO alone (Figure 4B, compare b-Cat-ASO+6BIO with b-Cat-ASO; n = 3; p < 0.001). The mRNA expression data under the conditions of our experiment were congruent with the protein expression data (a reduction of 92%; b-Cat-ASO+6BIO versus 63% b-Cat-ASO; Figure 4E).…”