Pharmacologic Manipulation of Wnt Signaling and Cancer Stem Cells

Abstract

Wnt (Wingless-related integration site)-signaling orchestrates self-renewal programs in normal somatic stem cells as well as in cancer stem cells. Aberrant Wnt signaling is associated with a wide variety of malignancies and diseases. Although our understanding has increased tremendously over the past decade, therapeutic targeting of the dysregulated Wnt pathway remains a challenge. Here we review recent preclinical and clinical therapeutic approaches to target the Wnt pathway.

Keywords: Cancer stem cells; Clinical trial; Drug resistance; Self-renewal; Somatic stem cells; Wnt signaling.

Fig. 1

(a) “Wnt Off.” In the absence of Wnt ligands, a destruction complex composed of Axin-1 and its tumor suppressor partners Adenomtous Polyposis Coli (APC), Glycogen synthase kinase 3 beta (GSK3B), and Casein kinase 1 (CK1α) is formed. The destruction complex phosphorylates ß-catenin and targets it for proteasomal degradation, regulating the cytoplasmic level of ß-catenin. (b) “Wnt On.” Wnt ligands bind to the Frizzled/Lrp5/6 (Low density lipoprotein receptor-related proteins 5 or 6) receptors leading to the phosphorylation of a negative regulator of the destruction complex, Dishevelled (Dvl). Dvl recruits Axin, inhibiting its interaction with other components of the destruction complex. ß-catenin is then free to accumulate in the cytoplasm and translocates to the nucleus, where it activates the transcription of Wnt target genes after association with transcription factors of the TCF/Lef family and co-activators such as CBP (cyclic AMP response element-binding protein) and p300. Arrows indicate activation/induction; blunt ended lines indicate inhibition/blockade

Fig. 2

(a) Noncanonical Wnt-signaling: Noncanonical Wnt/PCP (planar cell polarity) pathway. Wnt ligand binding to frizzled receptors leads to activation of Dishevelled (Dvl), which recruits DAAM1 (Dishevelled associated activator of morphogenesis 1), enhancing the stimulation of GTPases Rac (Ras-related C3 botulinum toxin substrate), and RHOA (Ras homolog gene family member A), leading to actin cytoskeleton rearrangement. In addition, Dvl activates Rac and finally JNK (c-Jun-N-terminal-kinase) thereby modulating cell migration. (b) Noncanonical Wnt/calcium pathway. Wnt ligands bind to Frizzled receptors and Ror/Ryk co-receptors, activating Dvl and trimeric G-proteins (Gα, β, γ). This leads to the generation of IP3 (inositol 1,4,5-triphosphate) and DAG2 (diacylglycerol) through PLC (Phospholipase C) activation. IP3 triggers the release of calcium ions (Ca²⁺) from the endoplasmic reticulum activating calmodulin and subsequently CAMKII (calcium/calmodulin-dependent kinase II), TAK-1 (TGF-β activated kinase 1), and NLK (Nemo-like kinase), thereby inhibiting the canonical Wnt pathway. Moreover, calmodulin activation stimulates calcineurin and NFAT (Nuclear Factor of Activated T-cells) involved in adhesion and migration processes. This pathway activates also PKC (Protein Kinase C) and Cdc42 (cell division control protein 42), rearranging the actin cytoskeleton. Arrows indicate activation; blunt ended lines indicate inhibition/blockade

Fig. 3

Modulators of the Wnt signaling pathway. The Wnt signaling pathway can be modulated with a wide variety of drugs currently in preclinical studies, in clinical trial or already approved (see text and Table 2). These drugs act at different levels in the Wnt pathway: Wnt receptors (OMP-18R5, OMP-54F28, Foxy-5, and ETC-961), Wnt posttranslational modification and secretion (LGK974 and ETC-159), tankyrase inhibitors (XAV-939 and IWR-1), Dvl inhibitors (Sulindac, NSC668036 and 3289–8625), β-catenin indirect modulators (Celecoxib and Sulindac), and inhibitors of β-catenin/CBP interaction (ICG-001 and PRI-724). Arrows indicate activation; blunt ended lines indicate inhibition/blockade