Targeting Wnt signaling in colorectal cancer. A Review in the Theme: Cell Signaling: Proteins, Pathways and Mechanisms

Abstract

The evolutionarily conserved Wnt signaling pathway plays essential roles during embryonic development and tissue homeostasis. Notably, comprehensive genetic studies in Drosophila and mice in the past decades have demonstrated the crucial role of Wnt signaling in intestinal stem cell maintenance by regulating proliferation, differentiation, and cell-fate decisions. Wnt signaling has also been implicated in a variety of cancers and other diseases. Loss of the Wnt pathway negative regulator adenomatous polyposis coli (APC) is the hallmark of human colorectal cancers (CRC). Recent advances in high-throughput sequencing further reveal many novel recurrent Wnt pathway mutations in addition to the well-characterized APC and β-catenin mutations in CRC. Despite attractive strategies to develop drugs for Wnt signaling, major hurdles in therapeutic intervention of the pathway persist. Here we discuss the Wnt-activating mechanisms in CRC and review the current advances and challenges in drug discovery.

Keywords: Wnt signaling pathway; adenomatous polyposis coli; colorectal cancer; drug targeting; small molecules; β-catenin.

Fig. 1.

Schematic representation of the Wnt signaling pathway with selected inhibitors. Wnt ligands are palmitoylated by the acyltransferase porcupine in the endoplasmic reticulum and transported to the Golgi complex. The transmembrane protein Wntless facilitates the subsequent transfer of Wnt ligands to the plasma membrane for secretion. β-Catenin, the key effector of Wnt signaling, will be constantly degraded by the destruction complex in the absence of Wnt. Casein kinase 1 (CK1) and glycogen synthase kinase 3β (GSK3β) in the complex phosphorylate β-catenin, which is then recognized by the E3-ligase β-TrCP for ubiquitination and proteosomal degradation. Upon Wnt ligand engagement of the Frizzled and low-density lipoprotein-related protein (LRP) receptors, the destruction complex will be inhibited, and the free cytosolic β-catenin will be translocated to the nucleus. Within the nucleus, β-catenin binds to the T cell factor (TCF) transcription factor together with other coactivators such as cAMP-response element-binding protein-binding protein (CBP) and p300 to regulate Wnt target gene transcription. The membrane-bound E3 ligases RNF43/ZNRF3 are Wnt negative feedback targets that will suppress Wnt signaling by removing Frizzled receptors from the cell surface and neutralizing the Wnt agonist R-spondin/leucine-rich repeat-containing G protein-coupled receptor (LGR) complex formation. Mutations in different Wnt signaling components (represented with red arrows) are frequently observed in colorectal cancers and have been found to cause pathway deregulation and tumorigenesis. Inhibitors targeting Wnt signaling at different cellular levels of the cascade are summarized in green boxes. LEF, lymphoid enhancer-binding factor; IWP, inhibitor of Wnt production; APC, adenomatous polyposis coli; TNK, tankyrase; DVL, Dishevelled.

Fig. 2.

Negative modulators of the Wnt signaling pathway. COX, cyclooxygenase; EGCG, epigallocatechin gallate. See Supplemental Material for references (available online at the journal website).