Browse
Submit Data
Databases
API
Help

Dataset Information

31 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Wnt signaling in cancer: therapeutic targeting of Wnt signaling beyond ?-catenin and the destruction complex.

ABSTRACT: Wnt/?-catenin signaling is implicated in many physiological processes, including development, tissue homeostasis, and tissue regeneration. In human cancers, Wnt/?-catenin signaling is highly activated, which has led to the development of various Wnt signaling inhibitors for cancer therapies. Nonetheless, the blockade of Wnt signaling causes side effects such as impairment of tissue homeostasis and regeneration. Recently, several studies have identified cancer-specific Wnt signaling regulators. In this review, we discuss the Wnt inhibitors currently being used in clinical trials and suggest how additional cancer-specific regulators could be utilized to treat Wnt signaling-associated cancer.

SUBMITTER: Jung YS

PROVIDER: S-EPMC7062731 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Wnt signaling in cancer: therapeutic targeting of Wnt signaling beyond β-catenin and the destruction complex.

Jung Youn-Sang YS Park Jae-Il JI

Experimental & molecular medicine 20200210 2

Wnt/β-catenin signaling is implicated in many physiological processes, including development, tissue homeostasis, and tissue regeneration. In human cancers, Wnt/β-catenin signaling is highly activated, which has led to the development of various Wnt signaling inhibitors for cancer therapies. Nonetheless, the blockade of Wnt signaling causes side effects such as impairment of tissue homeostasis and regeneration. Recently, several studies have identified cancer-specific Wnt signaling regulators. I ...[more]

PMID: 32037398

Similar Datasets

Therapeutic strategies targeting Wnt/β‑catenin signaling for colorectal cancer (Review).

Project description:Colorectal cancer (CRC) is one of the most common carcinomas. Although great progress has been made in recent years, CRC survival remains unsatisfactory due to high metastasis and recurrence. Understanding the underlying molecular mechanisms of CRC tumorigenesis and metastasis has become increasingly important. Recently, aberrant Wnt/β‑catenin signaling has been reported to be strongly associated with CRC tumorigenesis, metastasis and recurrence. Therefore, the Wnt/β‑catenin signaling pathway has potential value as a therapeutic target for CRC. In the present review, the dysregulation of this pathway in CRC and the promoting or suppressing function of therapeutic targets on CRC were explored. In addition, the interaction between this pathway and epithelial‑mesenchymal transition (EMT), cell stemness, mutations, metastasis‑related genes and tumor angiogenesis in CRC cells were also investigated. Numerous studies on this pathway may help identify the potential diagnostic and prognostic markers and therapeutic targets for CRC.

| S-EPMC8589460 | biostudies-literature

Destruction complex dynamics: Wnt/?-catenin signaling alters Axin-GSK3? interactions in vivo.

Project description:The central regulator of the Wnt/?-catenin pathway is the Axin/APC/GSK3? destruction complex (DC), which, under unstimulated conditions, targets cytoplasmic ?-catenin for degradation. How Wnt activation inhibits the DC to permit ?-catenin-dependent signaling remains controversial, in part because the DC and its regulation have never been observed in vivo Using bimolecular fluorescence complementation (BiFC) methods, we have now analyzed the activity of the DC under near-physiological conditions in Drosophila By focusing on well-established patterns of Wnt/Wg signaling in the developing Drosophila wing, we have defined the sequence of events by which activated Wnt receptors induce a conformational change within the DC, resulting in modified Axin-GSK3? interactions that prevent ?-catenin degradation. Surprisingly, the nucleus is surrounded by active DCs, which principally control the degradation of ?-catenin and thereby nuclear access. These DCs are inactivated and removed upon Wnt signal transduction. These results suggest a novel mechanistic model for dynamic Wnt signal transduction in vivo.

| S-EPMC6633605 | biostudies-literature

Understanding How Wnt Influences Destruction Complex Activity and ?-Catenin Dynamics.

Project description:Despite extensive research on the canonical Wnt signaling pathway, the mechanism by which this signal downregulates the activity of destruction complexes and inhibits ?-catenin degradation remains controversial. In particular, recent attention has focused on two main competing mechanisms-inhibition of phosphorylation and inhibition of ubiquitination. Our combined experimental and theoretical analysis demonstrates that the disassembly of a fraction of the intracellular destruction complexes results in the partial inhibition of both ?-catenin phosphorylation and ubiquitination. This inhibition is spatially patterned, consistent with the relocalization of some destruction complexes to the cellular membrane upon Wnt stimulation. Moreover, in contrast to the generally accepted view that the destruction complex is highly processive, our analysis supports a distributive model, in which ?-catenin can dissociate from the complex between sequential phosphorylation events. Understanding the fundamental mechanism by which Wnt signaling is regulated provides a rational basis for tuning the pathway for scientific and therapeutic purposes.

| S-EPMC6137275 | biostudies-literature

Targeting the Wnt/β-catenin signaling pathway in cancer.

Project description:The aberrant Wnt/β-catenin signaling pathway facilitates cancer stem cell renewal, cell proliferation and differentiation, thus exerting crucial roles in tumorigenesis and therapy response. Accumulated investigations highlight the therapeutic potential of agents targeting Wnt/β-catenin signaling in cancer. Wnt ligand/ receptor interface, β-catenin destruction complex and TCF/β-catenin transcription complex are key components of the cascade and have been targeted with interventions in preclinical and clinical evaluations. This scoping review aims at outlining the latest progress on the current approaches and perspectives of Wnt/β-catenin signaling pathway targeted therapy in various cancer types. Better understanding of the updates on the inhibitors, antagonists and activators of Wnt/β-catenin pathway rationalizes innovative strategies for personalized cancer treatment. Further investigations are warranted to confirm precise and secure targeted agents and achieve optimal use with clinical benefits in malignant diseases.

| S-EPMC7716495 | biostudies-literature

APC controls Wnt-induced ?-catenin destruction complex recruitment in human colonocytes.

Project description:Wnt/?-catenin signaling is essential for intestinal homeostasis and is aberrantly activated in most colorectal cancers (CRC) through mutation of the tumor suppressor Adenomatous Polyposis Coli (APC). APC is an essential component of a cytoplasmic protein complex that targets ?-catenin for destruction. Following Wnt ligand presentation, this complex is inhibited. However, a role for APC in this inhibition has not been shown. Here, we utilized Wnt3a-beads to locally activate Wnt co-receptors. In response, the endogenous ?-catenin destruction complex reoriented toward the local Wnt cue in CRC cells with full-length APC, but not if APC was truncated or depleted. Non-transformed human colon epithelial cells displayed similar Wnt-induced destruction complex localization which appeared to be dependent on APC and less so on Axin. Our results expand the current model of Wnt/?-catenin signaling such that in response to Wnt, the ?-catenin destruction complex: (1) maintains composition and binding to ?-catenin, (2) moves toward the plasma membrane, and (3) requires full-length APC for this relocalization.

| S-EPMC7031393 | biostudies-literature

Regulation of Transcription Factor SP1 by the ?-Catenin Destruction Complex Modulates Wnt Response.

Project description:The ubiquitous transcription factor specificity protein 1 (SP1) is heavily modified posttranslationally. These modifications are critical for switching its functions and modulation of its transcriptional activity and DNA binding and stability. However, the mechanism governing the stability of SP1 by cellular signaling pathways is not well understood. Here, we provide biochemical and functional evidence that SP1 is an integral part of the Wnt signaling pathway. We identified a phosphodegron motif in SP1 that is specific to mammals. In the absence of Wnt signaling, glycogen synthase kinase 3? (GSK3?)-mediated phosphorylation and ?-TrCP E3 ubiquitin ligase-mediated ubiquitination are required to induce SP1 degradation. When Wnt signaling is on, SP1 is stabilized in a ?-catenin-dependent manner. SP1 directly interacts with ?-catenin, and Wnt signaling induces the stabilization of SP1 by impeding its interaction with ?-TrCP and axin1, components of the destruction complex. Wnt signaling suppresses ubiquitination and subsequent proteosomal degradation of SP1. Furthermore, SP1 regulates Wnt-dependent stability of ?-catenin and their mutual stabilization is critical for target gene expression, suggesting a feedback mechanism. Upon stabilization, SP1 and ?-catenin cooccupy the promoters of TCFL2/?-catenin target genes. Collectively, this study uncovers a direct link between SP1 and ?-catenin in the Wnt signaling pathway.

| S-EPMC6206460 | biostudies-literature

Testing models of the APC tumor suppressor/?-catenin interaction reshapes our view of the destruction complex in Wnt signaling.

Project description:The Wnt pathway is a conserved signal transduction pathway that contributes to normal development and adult homeostasis, but is also misregulated in human diseases such as cancer. The tumor suppressor adenomatous polyposis coli (APC) is an essential negative regulator of Wnt signaling inactivated in >80% of colorectal cancers. APC participates in a multiprotein "destruction complex" that targets the proto-oncogene ?-catenin for ubiquitin-mediated proteolysis; however, the mechanistic role of APC in the destruction complex remains unknown. Several models of APC function have recently been proposed, many of which have emphasized the importance of phosphorylation of high-affinity ?-catenin-binding sites [20-amino-acid repeats (20Rs)] on APC. Here we test these models by generating a Drosophila APC2 mutant lacking all ?-catenin-binding 20Rs and performing functional studies in human colon cancer cell lines and Drosophila embryos. Our results are inconsistent with current models, as we find that ?-catenin binding to the 20Rs of APC is not required for destruction complex activity. In addition, we generate an APC2 mutant lacking all ?-catenin-binding sites (including the 15Rs) and find that a direct ?-catenin/APC interaction is also not essential for ?-catenin destruction, although it increases destruction complex efficiency in certain developmental contexts. Overall, our findings support a model whereby ?-catenin-binding sites on APC do not provide a critical mechanistic function per se, but rather dock ?-catenin in the destruction complex to increase the efficiency of ?-catenin destruction. Furthermore, in Drosophila embryos expressing some APC2 mutant transgenes we observe a separation of ?-catenin destruction and Wg/Wnt signaling outputs and suggest that cytoplasmic retention of ?-catenin likely accounts for this difference.

| S-EPMC4125400 | biostudies-literature

Identification of targets of the Wnt pathway destruction complex in addition to beta-catenin.

Project description:The proteasomal degradation of beta-catenin mediated by the glycogen synthase kinase 3beta (GSK3beta) and destruction complex is the central step in the canonical Wnt signaling pathway. However, that there are branches of Wnt signaling pathways that do not depend on beta-catenin/Tcf-mediated transcription activation has long been understood. In this study, we hypothesized that there are many more GSK3 and destruction complex-dependent proteolytic target proteins that mediate Wnt signaling in the cell. To test this hypothesis, we have developed and carried out a screen for such candidate proteins using an in vitro expression cloning technique and biochemical reconstitution of Wnt signaling in Xenopus egg cytoplasmic extracts. Forty-two proteins have been identified as potential candidates for GSK3-regulated phosphorylation, proteasomal degradation, or both, of which 12 are strong candidates for Wnt-pathway-regulated degradation. Some of them have been reported to interact with beta-catenin and implicated in the canonical Wnt signaling pathway, and other targets identified include proteins with various cellular functions such as RNA processing, cytoskeletal dynamics, and cell metabolism. Thus, we propose that Wnt/GSK3/destruction complex signaling regulates multiple target proteins to control a broad range of cellular activities in addition to beta-catenin-mediated transcription activation.

| S-EPMC2663984 | biostudies-literature

Targeting CDH17 suppresses tumor progression in gastric cancer by downregulating Wnt/β-catenin signaling.

Project description:PurposeGastric cancer remains one of the leading causes of cancer death worldwide. Patients usually present late with local invasion or metastasis, for which there are no effective therapies available. Following previous studies that identified the adhesion molecule Cadherin-17(CDH17) as a potential marker for gastric carcinoma, we performed proof-of-principle studies to develop rational therapeutic approaches targeting CDH17 for treating this disease.MethodsImmunohistochemistry was used to study the expression of CDH17 in 156 gastric carcinomas, and the relationship between survival and CDH17 expression was studied by multivariate analyses. The effect of RNA interference-mediated knockdown of CDH17 on proliferation of gastric carcinoma cell lines was examined in vitro and in vivo, as well as the effects on downstream signaling by immunoblotting.ResultsCDH17 was consistently up-regulated in human gastric cancers, and overall survival in patients with CDH17 upregulation was poorer than in those without expression of this gene (5 yrs overall survival rate 29.0% vs. 45.0%, P<0.01). Functional assays demonstrated that CDH17 knockdown inhibited cell proliferation, adhesion, migration, invasion, clonogenicity and induce G0/G1 arrest. In mice, shRNA-mediated CDH17 knockdown markedly inhibits tumor growth; intratumoral injection of CDH17 shRNAs results in significant antitumor effects on transplanted tumor models. The antitumor mechanisms underlying CDH17 inhibition involve inactivation of Wnt/β-catenin signaling.ConclusionOur results identify CDH17 as a biomarker of gastric carcinoma and attractive therapeutic target for this aggressive malignancy.

| S-EPMC3598811 | biostudies-literature

Inhibition of oncogenic Wnt signaling through direct targeting of ?-catenin.

Project description:Aberrant activation of signaling by the Wnt pathway is strongly implicated in the onset and progression of numerous types of cancer. Owing to the persistent dependence of these tumors on Wnt signaling for growth and survival, inhibition of this pathway is considered an attractive mechanism-based therapeutic approach. Oncogenic activation of Wnt signaling can ensue from a variety of distinct aberrations in the signaling pathway, but most share the common feature of causing increased cellular levels of ?-catenin by interfering with its constitutive degradation. ?-Catenin serves as a central hub in Wnt signaling by engaging in crucial protein-protein interactions with both negative and positive effectors of the pathway. Direct interference with these protein-protein interactions is a biologically compelling approach toward suppression of ?-catenin hyperactivity, but such interactions have proven intransigent with respect to small-molecule targeting. Hence ?-catenin remains an elusive target for translational cancer therapy. Here we report the discovery of a hydrocarbon-stapled peptide that directly targets ?-catenin and interferes with its ability to serve as a transcriptional coactivator for T-cell factor (TCF) proteins, the downstream transcriptional regulators of the Wnt pathway.

| S-EPMC3497784 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data