New DrugsTargeting the Wnt/beta-catenin pathway in cancer: Update on effectors and inhibitors
Graphical abstract
Introduction
The Wnt family is a group of proteins implicated in many cellular functions: organ formation, stem cell renewal, and cell survival [1]. In humans, the Wnt family consists of cysteine rich glycoproteins that act as ligands for as many as fifteen receptors and co-receptors [2]. Extracellular Wnt can trigger varied intra-cellular signal transduction pathways, like the Wnt/beta-catenin dependent or canonical pathway and the beta-catenin-independent or non-canonical pathway (Figs. 1 and 2b). Examples of the beta-catenin-independent pathway include the Wnt/Ca 2 + pathway as well as the Planar Cell Polarity pathway (PCP) [3]. The beta-catenin-dependent signaling pathway is triggered by the binding of Wnt ligand to the LRP-5/6 receptors (low-density lipoprotein receptor) and Frizzled receptors. This in turn activates Disheveled (DVL), causing recruitment of the complex (Axin, GSK-3 beta, CK1, APC) to the receptor. [4], [5], [6]. The Wnt – Frizzled-Axin -LRP-5/6complex sequesters cytosolic GSK-3 beta rendering it incapable of phosphorylating beta-catenin. There is accumulation of un-phosphorylated beta-catenin in the cytosol which migrates to the nucleus, interacting there with T cell-specific factor (TCF)/lymphoid enhancer-binding factor (LEF) and co-activators, like Pygopus (Pygo) and Bcl-9, to turn on the Wnt target genes such as c-Myc, cyclin D1 and Cdkn1a [6].
Without Wnt, the beta-catenin in the cytosol undergoes phosphorylation by GSK-3 beta and CK1 and subsequent sequestration in the beta-catenin destruction complex, (APC, GSK-3 beta, CK1, Axin). This phosphorylated complex allows for the E3 ubiquitin ligase called beta-TrCP to attach to the beta-catenin at a binding site, that enhances its ubiquitination leading to subsequent proteasomal degradation [7], [8] (Fig. 2a). One of the Non-canonical Wnt pathways includes the PCP or Planar cell polarity pathway. This can be initiated by Wnt interaction with Frizzled receptors, with co-receptors RYK and ROR which control the activity of small GTPases such as RhoA that play a role in regulation of the remodeling of the cytoskeleton [8] (Fig. 2b). Wnt interaction with Frizzled leads to Dvl activation [8]. myosin and the Rho-associated kinase (ROCK) are activated by Rho GTPase, altering the mechanism of actin and cytoskeleton rearrangement. There is in tandem activation of Rac GTPase and activated Rac then stimulates JNK activity (c-Jun N-terminal kinase) [9].
In the Wnt/Ca 2 + pathway, activated by Wnt 5A, the frizzled FZD2 cleaves guanine nucleotide binding protein (G-protein), into protein beta/gamma subunits G-protein alpha-t2 causing Ca 2+ to be released into the cytosol promoting differentiation in the neuronal system. Calcium activates CaMK II and Calmodulin, enhancing phosphorylation of Tcf/Lef (T-cell factor and lymphoid enhancer factor) thus suppressing the canonical Wnt pathway. The mechanisms by which Wnt5a can also interact via the canonical pathway are not completely mapped out though it is speculated that the LRP5 co-receptor is activated along with FZD4 and FZD5 receptors [10], [11], [12], [13], [14].
Section snippets
Axin and APC-negative regulators of Wnt
Axin serves as a scaffold protein recruiting GSK3β and CKIα (caspase kinase alpha) along with APC to form a complex with beta-catenin resulting in beta-catenin phosphorylation, ultimately causing its degradation. Axin also plays a key role in Wnt signaling initiation. PPPSP motifs on the cytoplasmic tail of LRP6 are phosphorylated upon Wnt activation. This in turn causes recruitment of Axin complexes to the membrane destabilizing beta-catenin complex in the cytoplasm. Axin is post
RNF43 and RSPO signaling modulation of Wnt
RNF43 (Ring finger protein 43) and the homolog ZNRF3 are transmembrane E3 ligases that dispose of the surface Wnt receptors and promote FZD receptor turnover. R-spondins or RSPO’s are a group of proteins that together bind to the extracellular domains of LGR4/5 and RNF43/ZNRF3, resulting in increased cell surface FZD receptors as this binding causes ubiquitination and clearance of RNF43/ZNRF3 [21], [22].
Wnt and Notch signaling pathway cross-talk
It is thought that the Wnt-beta catenin pathways and Notch pathways interact for Drosophila wing development [23]. Importantly, the Notch target gene Hes1, which encodes a strong basic helix–loop–helix (bHLH) transcriptional repressor, is regulated by beta-catenin-mediated Wnt signaling [24]. There is some evidence that direct interaction between beta-catenin and TCF activates Notch in colorectal cancer cells through regulation of Jagged1 expression. Βeta-catenin interaction with Notch-1 leads
Wnt-Sonic Hedgehog pathway cross-talk
The Sonic hedgehog (SHH) pathway plays a vital role in embryogenesis. It has a critical role in the development of neural structures. Activated, the Sonic hedgehog (SHH) attaches to Patch receptors leading to the increased activity of Smoothened receptors (Smo). This in turn causes the transcription of glioma-associated oncogenes homologs (Gli1/2/3) [26]. There is evidence that SHH-mediated tumorigenesis can be inhibited by Wnt. Both GSK3β and CK1α phosphorylate Gli3 that leads to Gli3
Wnt in cancers
Wnt pathway is upregulated in both MSI (microsatellite instable) and MSS (microsatellite stable) colorectal cancers [66]. Normally activated at the bottom of the intestinal crypts, Wnt is critical to cell repair and maintenance of stem cell functions. The primary mechanism of Wnt pathway activation is the loss of function of APC which functions as a negative regulator. Wnt/beta-catenin signaling is activated by truncated APC protein that negates destruction complex-mediated beta-catenin
Porcupine inhibitors (Fig. 2a)
Porcupine (PORCN) is a membrane-bound O-acyltransferase (MBOAT) important for the secretion of Wnt ligands because it supplies the palmitoyl group to Wnt proteins, a crucial step for Wnt ligand secretion [76].
The Porcupine-selective inhibitor LGK974 blocks Wnt signaling and tumor growth in vivo [40]. Head and neck squamous cell carcinoma (HNSCC) cell lines carrying NOTCH1 mutations that are inactivating are particularly sensitive to inhibition by LGK974 [77]. Porcupine is a Wnt pathway target
Disclosures
Dr. Kurzrock receives research funding from Genentech, Merck, Serono, Pfizer, Sequenom, Foundation Medicine, and Guardant, as well as consultant fees from X Biotech, and Actuate Therapeutics and has an ownership interest in Curematch Inc.
Funding
Funded in part by National Cancer Institute grant P30 CA016672 and the Joan and Irwin Jacobs Fund philanthropic fund.
Conflict of Interest Statement
Dr. Kurzrock has research funding from Genentech, Merck Serono, Pfizer, Sequenom, Foundation Medicine, and Guardant Health, as well as consultant fees from XBiotech and Actuate Therapeutics and an ownership interest in Novena, Inc. and Curematch, Inc.
References (100)
- et al.
Wnt/β-catenin signaling: components, mechanisms, and diseases
Dev Cell
(2009 Jul 21) - et al.
GSK3: a multifaceted kinase in Wnt signaling
Trends Biochem Sci
(2010 Mar 31) - et al.
Wnt signaling: multiple pathways, multiple receptors, and multiple transcription factors
J Biol Chem
(2006 Aug 11) - et al.
Wnt/β-catenin signaling induces the expression and activity of βTrCP ubiquitin ligase receptor
Mol Cell
(2000 May 31) - et al.
Wnt and calcium signaling: β-catenin-independent pathways
Cell Calcium
(2005 Oct 31) - et al.
A novel set of Wnt-Frizzled fusion proteins identifies receptor components that activate β-catenin-dependent signaling
J Biol Chem
(2002 Sep 20) - et al.
Dishevelled promotes Wnt receptor degradation through recruitment of ZNRF3/RNF43 E3 ubiquitin ligases
Mol Cell
(2015 May 7) - et al.
Downregulation of β-catenin by human Axin and its association with the APC tumor suppressor, β-catenin and GSK3β
Curr Biol
(1998 May 7) - et al.
Linking colorectal cancer to Wnt signaling
Cell
(2000 Oct 13) - et al.
The Notch intracellular domain integrates signals from Wnt, Hedgehog, TGFβ/BMP and hypoxia pathways. Biochimica et Biophysica Acta (BBA)-Molecular
Cell Res
(2016 Feb 29)
Wnt5a controls Notch1 signaling through CaMKII-mediated degradation of the SMRT corepressor protein
J Biol Chem
Suppressor of fused negatively regulates beta-catenin signaling
J Biol Chem
XAV939, a tankyrase 1 inhibitior, promotes cell apoptosis in neuroblastoma cell lines by inhibiting Wnt/β-catenin signaling pathway
J Exp Clin Cancer Res
Therapeutic targets in the Wnt signaling pathway: Feasibility of targeting TNIK in colorectal cancer
Pharmacol Ther
Targeting the Wnt pathway in human cancers: Therapeutic targeting with a focus on OMP-54F28
Pharmacol Ther
In vivo and in vitro effects of a novel anti-Dkk1 neutralizing antibody in multiple myeloma
Bone
Inhibition of Wnt/β-catenin pathway by niclosamide: A therapeutic target for ovarian cancer
Gynecol Oncol
The safety and activity of BMS-906024, a gamma secretase inhibitor (GSI) with anti-notch activity, in patients with relapsed T-cell acute lymphoblastic leukemia (T-ALL): initial results of a phase 1 trial
Blood
Safety and early evidence of activity of a first-in-human phase I study of the novel cancer stem cell (CSC) targeting antibody OMP-52M51 (anti-Notch1) administered intravenously to patients with certain advanced solid tumors
Eur J Cancer
Wnt/β-catenin pathway activation is enriched in basal-like breast cancers and predicts poor outcome
Am J Pathol
Wnt/β-catenin signaling regulates cancer stem cells in lung cancer A549 cells
Biochem Biophys Res Commun
Wnt-Pathway Directed Compound Targets Blast Crisis and Chronic Phase CML Leukemia Stem Progenitors
Blood
Takes RP. Moving towards personalised therapy in head and neck squamous cell carcinoma through analysis of next generation sequencing data
Eur J Cancer
A monoclonal antibody against Wnt-1 induces apoptosis in human cancer cells
Neoplasia
Discovery and characterization of a small molecule inhibitor of the PDZ domain of dishevelled
J Biol Chem
Small-molecule antagonists of the oncogenic Tcf/β-catenin protein complex
Cancer Cell
Results of a phase 1 trial combining ridaforolimus and MK-0752 in patients with advanced solid tumours
Eur J Cancer
Targeting GLI factors to inhibit the Hedgehog pathway
Trends Pharmacol Sci
Combination of tyrosine kinase inhibitor with β-Catenin/CBP modulator C82 reverses TKI resistance, eradicates quiescent CML stem/progenitors cells, and overcomes MSC-associated microenvironmental protection
Blood
Dysregulation of Wnt/β-catenin signaling in gastrointestinal cancers
Gastroenterology
Evolution of the Wnt pathways
Wnt Signaling
Wnt proteins are lipid-modified and can act as stem cell growth factors
Nature
Wnt induces LRP6 signalosomes and promotes disheveled-dependent LRP6 phosphorylation
Science
Wnt-5a inhibits the canonical Wnt pathway by promoting GSK-3–independent β-catenin degradation
J Cell Biol
Noncanonical Wnt5a enhances Wnt/β-catenin signaling during osteoblastogenesis
Sci Rep
Frizzled and LRP5/6 Receptors for Wnt/β-Catenin Signaling
Cold Spring Harbor Perspect Biol
Gβγ activates GSK3 to promote LRP6-mediated β-catenin transcriptional activity
Sci Signal
Wnt stabilization of β-catenin reveals principles for morphogen receptor-scaffold assemblies
Science
Initiation of Wnt signaling: control of Wnt coreceptor Lrp6 phosphorylation/activation via frizzled, dishevelled and axin functions
Development
Differential role of Axin RGS domain function in Wnt signaling during anteroposterior patterning and maternal axis formation
PLoS ONE
Adenomatous polyposis coli (APC): a multi-functional tumor suppressor gene
J Cell Sci
The E3 ligase RNF43 inhibits Wnt signaling downstream of mutated b-catenin by sequestering TCF4 to the nuclear membrane
Sci Signal
Structural and molecular basis of ZNRF3/RNF43 transmembrane ubiquitin ligase inhibition by the Wnt agonist R-spondin
Nature Commun
Wnt-Notch signalling crosstalk in development and disease
Cell Mol Life Sci
Crosstalk between Wnt/β-catenin and Hedgehog/Gli signaling pathways in colon cancer and implications for therapy
Cancer Biol Ther
Evidence for the direct involvement of beta TrCP in Gli3 protein processing
Proc Natl Acad Sci U S A
Tankyrase-targeted therapeutics: expanding opportunities in the PARP family
Nat Rev Drug Discovery
Tankyrase inhibitors attenuate WNT/β-catenin signaling and inhibit growth of hepatocellular carcinoma cells
Oncotarget
The tankyrase-specific inhibitor JW74 affects cell cycle progression and induces apoptosis and differentiation in osteosarcoma cell lines
Cancer Med
Inhibition of the Wnt palmitoyl transferase porcupine suppresses cell growth and downregulates the Wnt/β-catenin pathway in gastric cancer
Oncol Lett
Cited by (748)
The role of proteasomes in tumorigenesis
2024, Genes and DiseasesBreast cancer stem cells as novel biomarkers
2024, Clinica Chimica ActaThe dual roles of circRNAs in Wnt/β-Catenin signaling and cancer progression
2024, Pathology Research and PracticeGCF2 mediates nicotine-induced cancer stemness and progression in hepatocellular carcinoma
2024, Ecotoxicology and Environmental Safety