Small-Molecule Inhibitors of Wnt Signaling Pathway: Towards Novel Anticancer Therapeutics

Zheng, Shilong; Liu, Jiawang; Wu, Yanyuan; Huang, Tien L.; Wang, Guangdi

doi:10.4155/fmc.15.159

Cited by 18 publications

(19 citation statements)

References 88 publications

(124 reference statements)

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“…Our data suggest several therapeutic avenues, but these would likely be divided into treatments that either secure dormancy, i.e.- antagonize reawakening, or that induce large scale reawakening in a neoadjuvant setting, linked to standard chemotherapies prescribed for TNBC. Examples of reawakening suppressors might include small molecule inhibitors of MYC (49) or Nutlin-3a to normalize mutant p53 function (50), whereas inducers of reawakening might include inhibitors of WNT3 signaling (51, 52) or p38 kinase activity (53).…”

Section: Resultsmentioning

confidence: 99%

Identification of Genes Regulating Breast Cancer Dormancy in 3D Bone Endosteal Niche Cultures

McGrath

Panzica

Ransom

et al. 2019

Molecular Cancer Research

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Cancer tumor cell dormancy is a significant clinical problem in breast cancer (BrCa). We used a 3D in vitro model of the endosteal bone niche (EN), consisting of endothelial, bone marrow stromal cells and fetal osteoblasts in a 3D collagen matrix (GELFOAM™), to identify genes required for dormancy. Human triple-negative MDA-MB-231 BrCa cells, but not the bone-tropic metastatic variant, BoM1833, established dormancy in 3D-EN cultures in a p38-MAPK-dependent manner, whereas both cell types proliferated on 2D plastic or in 3D collagen alone. “Dormancy-reactivation suppressor genes” (DRSG) were identified using a genomic shRNA screen in MDA-MB-231 cells for gene knockdowns that induced proliferation in the 3D-EN. DSRG candidates enriched for genes controlling stem cell biology, neurogenesis, MYC targets, ribosomal structure and translational control. Several potential DRSG were confirmed using independent shRNAs, including BHLHE41, HBP1 and WNT3. Overexpression of the WNT3/a antagonists, secreted frizzled-related protein 2 or 4 (SFRP2/4), induced MDA-MB-231 proliferation in the EN. In contrast, overexpression of SFRP3, known not to antagonize WNT3/a, did not induce proliferation. Decreased WNT3 or BHLHE41 expression was found in clinical BrCa metastases compared to primary-site lesions, and the loss of WNT3 or BHLHE41 or gain of SFRP1, 2 and 4 in the context of TP53 loss/mutation correlated with decreased progression-free and overall survival.

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Section: Resultsmentioning

confidence: 99%

Identification of Genes Regulating Breast Cancer Dormancy in 3D Bone Endosteal Niche Cultures

McGrath

Panzica

Ransom

et al. 2019

Molecular Cancer Research

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“…2 ). Other experimental approaches to target the Wnt/β-catenin pathway that have been explored, but are beyond the scope of this review can be found in Anastas and Zheng and colleagues [ 122 , 123 ]. In summary, these three families of signaling pathways are potentially attractive targets for specific therapies designed to attack breast tumors, in particular TNBC.…”

Section: Cripto-1 Notch/csl and Wnt/β-catenin Signaling Members As mentioning

confidence: 99%

Developmental signaling pathways regulating mammary stem cells and contributing to the etiology of triple-negative breast cancer

Rangel

Bertolette

Castro

et al. 2016

Breast Cancer Res Treat

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Cancer has been considered as temporal and spatial aberrations of normal development in tissues. Similarities between mammary embryonic development and cell transformation suggest that the underlying processes required for mammary gland development are also those perturbed during various stages of mammary tumorigenesis and breast cancer (BC) development. The master regulators of embryonic development Cripto-1, Notch/CSL, and Wnt/β-catenin play key roles in modulating mammary gland morphogenesis and cell fate specification in the embryo through fetal mammary stem cells (fMaSC) and in the adult organism particularly within the adult mammary stem cells (aMaSC), which determine mammary progenitor cell lineages that generate the basal/myoepithelial and luminal compartments of the adult mammary gland. Together with recognized transcription factors and embryonic stem cell markers, these embryonic regulatory molecules can be inappropriately augmented during tumorigenesis to support the tumor-initiating cell (TIC)/cancer stem cell (CSC) compartment, and the effects of their deregulation may contribute for the etiology of BC, in particular the most aggressive subtype of BC, triple-negative breast cancer (TNBC). This in depth review will present evidence of the involvement of Cripto-1, Notch/CSL, and Wnt/β-catenin in the normal mammary gland morphogenesis and tumorigenesis, from fMaSC/aMaSC regulation to TIC generation and maintenance in TNBC. Specific therapies for treating TNBC by targeting these embryonic pathways in TICs will be further discussed, providing new opportunities to destroy not only the bulk tumor, but also TICs that initiate and promote the metastatic spread and recurrence of this aggressive subtype of BC.

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“…Therapeutic tools that modulate the Porcn function effectively in vitro and in vivo are attractive in the field of cancer therapy, regenerative medicine, and stem cell processing. Chemical inhibition by small molecules has been developed for Porcn modulation (Ho & Keller, 2015;Zheng, Liu, Wu, Huang, & Wang, 2015). Orally bioavailable small molecules F I G U R E 1 Sequence alignment of porcupine (Porcn) for Homo sapiens, Drosophila melanogaster, Caenorhabditis elegans, Mus musculus, Rattus norvegicus and Danio rerio (zebrafish).…”

Section: Introductionmentioning

confidence: 99%

“…Therapeutic tools that modulate the Porcn function effectively in vitro and in vivo are attractive in the field of cancer therapy, regenerative medicine, and stem cell processing. Chemical inhibition by small molecules has been developed for Porcn modulation (Ho & Keller, 2015; Zheng, Liu, Wu, Huang, & Wang, 2015). Orally bioavailable small molecules that inhibit Porcn catalytic activity and consequently Wnt palmitoleoylation disturb both canonical and non‐canonical Wnt signaling.…”

Section: Introductionmentioning

confidence: 99%

Application of porcupine inhibitors in stem cell fate determination

et al. 2020

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Porcupine (Porcn), a membrane‐bound O‐acyltransferase, is an endoplasmic reticulum‐located protein that has catalytic activity. Porcn is involved in post‐translational lipid modification of wingless‐Int (Wnt) proteins and serves as an indispensable step in the Wnt proper secretion and signaling. Small‐molecule inhibitors targeting Porcn catalytic function in vitro and in vivo are of great interest not only for treating cancer and fibrotic disorders but also in the field of regenerative medicine. Although a number of studies have been conducted, the exact role of Porcn in stem cell fate is not entirely clear. In some cases, Porcn inhibition declined differentiation rate, and in others, it induced stem cell differentiation toward specific lineages. In this review, we first elaborated the Porcn catalytic activity and its inhibitors. Then, we discussed about the recently reported results of Porcn inhibitors in stem cells self‐renewal and differentiation.

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Small-Molecule Inhibitors of Wnt Signaling Pathway: Towards Novel Anticancer Therapeutics

Abstract: Focusing on recent developments, we reviewed the small-molecule inhibitors targeting various components of Wnt signaling pathways and the progress from the discovery of lead compounds to highly potent inhibitors with significant therapeutic potential.

Cited by 18 publications

References 88 publications

Identification of Genes Regulating Breast Cancer Dormancy in 3D Bone Endosteal Niche Cultures

Identification of Genes Regulating Breast Cancer Dormancy in 3D Bone Endosteal Niche Cultures

Developmental signaling pathways regulating mammary stem cells and contributing to the etiology of triple-negative breast cancer

Application of porcupine inhibitors in stem cell fate determination

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