Aberrant canonical Wnt signaling: Phytochemical based modulation

BackgroundWnt signaling pathway plays a major role during development like gastrulation, axis formation, organ development and organization of body plan development. Wnt signaling aberration has been linked with various disease conditions like osteoporosis, colon cancer, hair follicle tumor, Leukemia, and Alzheimer's disease. Phytochemicals like flavonoid, glycosides, polyphenols, have been reported to directly target the markers of Wnt signaling in different disease models.PurposeThe study deals in detail about the different phytochemical targeting key players of Wnt signaling pathway in diseases like Cancer, Osteoporosis, and Alzheimer's disease. We have focused on the Pharmacological basis of disease alleviation by phytochemical specifically targeting the Wnt signaling markers in this study.MethodsThe study focused on the published articles from the preclinical rodent and invitro cell line studies related to Wnt signaling and Phytochemicals related to Cancer, Alzheimer's and Osteoporosis. The electronic databases Scopus, Web of Science and Pubmed database were used for the systematic search of literatures from 2005 up to 2019 using keywords Canonical Wnt signaling pathway, Cancer, Alzheimer's disease, Osteoporosis, Phytochemicals. The focus was to identify the target specific modulation of Wnt signaling mediated by phytochemicals.ResultsApproximately 30 phytochemicals of different class have been identified to modulate Wnt signaling pathway acting through Axin, β-catenin translocation, GSK-3β, AKT, Wif-1 in various experimental studies. The down regulation of Wnt signaling is observed in Cancer mostly colorectal cancer, breast cancer mediated through mutations in APC and Axin genes. Different class of Phytochemicals such as flavonoid, glycosides, polyphenol, alkaloids etc. have been found to target Wnt signaling markers and alleviate Cancer. Similarly, Up regulation of Wnt signaling has been reported in Osteoporosis and neurodegenerative disease like Alzheimer's disease.ConclusionThis review highlights the possibility of the Phytochemicals to target Wnt markers and its potential to either activate or deactivate the Wnt signaling pathway. It also describes the challenges in proper targeting of Wnt signaling and the potential risk and consequences of either up regulation or down regulation of the signaling pathway. This article highlights the possibility of Wnt signaling pathway as a therapeutic option in different diseases.     

Wnts and wing: Wnt signaling in vertebrate limb development and musculoskeletal morphogenesis

In the past twenty years, secreted signaling molecules of the Wnt family have been found to play a central role in controlling embryonic development from hydra to human. In the developing vertebrate limb, Wnt signaling is required for limb bud initiation, early limb patterning (which is governed by several well-characterized signaling centers), and, finally, late limb morphogenesis events. Wnt ligands are unique, in that they can activate several different receptor-mediated signal transduction pathways. The most extensively studied Wnt pathway is the canonical Wnt pathway, which controls gene expression by stabilizing beta-catenin in regulating a diverse array of biological processes. Recently, more attention has been given to the noncanonical Wnt pathway, which is beta-catenin-independent. The noncanonical Wnt pathway signals through activating Ca(2+) flux, JNK activation, and both small and heterotrimeric G proteins, to induce changes in gene expression, cell adhesion, migration, and polarity. Abnormal Wnt signaling leads to developmental defects and human diseases affecting either tissue development or homeostasis. Further understanding of the biological function and signaling mechanism of Wnt signaling is essential for the development of novel preventive and therapeutic approaches of human diseases. This review provides a critical perspective on how Wnt signaling regulates different developmental processes. As Wnt signaling in tumor formation has been reviewed extensively elsewhere, this part is not included in the review of the clinical significance of Wnt signaling.     

Increasingly complex: new players enter the Wnt signaling network

Wnt proteins can activate different intracellular signaling cascades in various organisms by interacting with receptors of the Frizzled family. The first identified Wnt signaling pathway, the Wnt/beta-catenin pathway, has been studied in much detail and is highly conserved among species. As to non-canonical Wnt pathways, the current situation is more nebulous partly because the intracellular mediators of this pathway are not yet fully understood and, in some cases, even identified. However, there are increasing data that prove the existence of non-canonical Wnt signaling and demonstrate its involvement in different developmental processes. In vertebrates, Wnt-11 and Wnt-5A can activate the Wnt/JNK pathway, which resembles the planar cell polarity pathway in Drosophila. The Wnt/Ca(2+)-pathway has only been described in Xenopus and zebrafish so far and it is unclear whether it also exists in other organisms. Two recent papers provide us with new insight into non-canonical Wnt signaling by (1) presenting a new intracellular mediator of non-canonical signaling in Xenopus1 and (2) implicating the existence of an additional non-canonical Wnt signaling pathway in flies.     

The Wnt signaling pathway has tumor suppressor properties in retinoblastoma

Retinoblastoma is a pediatric retinal tumor caused by mutational inactivation of the tumor suppressor pRb. Additional genetic changes, as yet unidentified, are believed to be required for tumor initiation. Mutations in the Wnt signaling pathway have been implicated in the pathogenesis of many cancers. Multiple Wnt pathway genes are expressed in the retina and the pRb and Wnt pathways interact biochemically, raising the possibility that alterations in the Wnt pathway contribute to retinoblastoma. Our studies showed that Wnt signaling activation significantly decreased the viability of retinoblastoma cell lines by inducing cell cycle arrest, which was associated with upregulated p53. Furthermore, immunolocalization of the Wnt signaling mediator beta-catenin in human and mouse retinoblastoma tissue indicated that canonical Wnt signaling is suppressed in tumors in vivo. These studies are consistent with the Wnt pathway acting as a tumor suppressor in retinoblastoma and suggest that loss of Wnt signaling is tumorigenic in the retina.     

The roles of canonical and non-canonical Wnt signaling in human de-differentiated articular chondrocytes

Osteoarthritis is the most prevalent form of arthritis in the world and it is becoming a major public health problem. Osteoarthritic chondrocytes undergo morphological and biochemical changes that lead to de-differentiation. The involvement of signaling pathways, such as the Wnt pathway, during cartilage pathology has been reported. Wnt signaling regulates critical biological processes. Wnt signals are transduced through at least three intracellular signaling pathways including the canonical Wnt/β-catenin pathway, the Wnt/Ca2 + pathway and the Wnt/planar cell polarity pathway. We investigated the involvement of the Wnt canonical and non-canonical pathways in human articular chondrocyte de-differentiation in vitro. Human articular chondrocytes were cultured through four passages with no treatment, or with sFRP3 treatment, an inhibitor of Wnt pathways, or with DKK1 treatment, an inhibitor of the canonical pathway. Chondrocyte-secreted markers and Wnt pathway components were analyzed using western blotting and qPCR. Inhibition of the Wnt pathway showed that the canonical Wnt signaling probably is responsible for inhibition of collagen II expression, activation of metalloproteinase 13 expression and regulation of Wnt7a and c-jun expression during chondrocyte de-differentiation in vitro. Our results also suggest that expressions of eNOS, Wnt5a and cyclinE1 are regulated by non-canonical Wnt signaling.     

Nuclear beta-catenin localization is not sufficient for canonical Wnt signaling activation in human meianoma cell lines

In most cases, advanced stages of melanoma are practically incurable due to high metastatic potential of tumor cells. Multiple observations support the idea that aberrations in Wnt signaling pathway play a significant role in melanoma development and progression. Canonical Wnt signaling activation results in stabilization and accumulation of the major effector molecule called beta-catenin. Mutations promoting beta-catenin stabilization and, thereby, activation of canonical Wnt signaling pathway are frequently found in different cancers, but rarely observed in melanomas. Nevertheless, beta-catenin nuclear and cytoplasmic accumulation is the feature of many human melanoma cell lines and original tumors. That is why, the aim of the investigation was to elucidate the relation between beta-catenin intracellular localization and activity status of Wnt signaling pathway in human melanoma cell lines. Ten human melanoma cell lines were characterized on the basis of the following parameters: canonical Wnt ligand expression, intracellular beta-catenin localization, and activity status of canonical Wnt signaling pathway. Here, it has been demonstrated that nuclear localization of beta-catenin does not always correspond to active status canonical Wnt signaling pathway. Moreover, in the majority of cell lines with nuclear beta-catenin canonical Wnt signaling can't be activated by exogenous expression of an appropriate ligand. Human melanoma cell lines differ in activity of canonical Wnt signaling pathway as well as in mechanisms of its regulation. Therefore, the pathway-targeted potential antineoplastic therapy requires the formation of a "molecular pattern of cancer" for localization of the defect in Wnt signaling cascade in the each case.     

BATF2对Wnt信号通路影响的研究

摘要wnt信号通路在各种生物体内高度进化保守,与癌症的发生发展密切相关。BATF2是一个新近发现的基因,研究表明其具有抑癌基因的作用。目前,BATF2与wnt信号通路的关系尚不清楚,该文用荧光素酶报告基因检测、Real－timePCR和Western blot发现BATF2能影响wnt信号通路。过表达BArF2可明显下调TCF4／p－catenin的转录活性和Wnt信号通路下游基因的表达,可以下调细胞核中的β-caenin。推测BATF2可能通过下调细胞核中的p－catenin来实现对wnt信号通路的下调。上述结果为抑制Wnt信号通路用于肿瘤治疗提供了一定的依据。     

WNT signaling in atrial fibrillation

The Wnt signaling pathway regulates physiological processes such as cell proliferation and differentiation, cell fate decisions, and stem cell maintenance and, thus, plays essential roles in embryonic development, but also in adult tissue homeostasis and repair. The Wnt signaling pathway has been associated with heart development and repair and has been shown to be crucially involved in proliferation and differentiation of progenitor cells into cardiomyocytes. The investigation of the role of the Wnt signaling pathway and the regulation of its expression/activity in atrial fibrillation has only just begun. The present minireview (I) provides original data regarding the expression of Wnt signaling components in atrial tissue of patients with atrial fibrillation or sinus rhythm and (II) summarizes the current state of knowledge of the regulation of Wnt signaling components’ expression/activity and the contribution of the various levels of the Wnt signal transduction pathway to the processes of the development, maintenance, and progression of atrial fibrillation.     

Wnt/beta-catenin signaling inhibits death receptor-mediated apoptosis and promotes invasive growth of HNSCC

The Wnt/beta-catenin signaling pathway plays a critical role in cell proliferation and oncogenesis. It has been found to be chronically activated in a variety of human cancers, including head and neck squamous cell carcinoma (HNSCC). Previously, we have found that the activation of the Wnt/beta-catenin signaling pathway inhibits mitochondria-mediated apoptosis. In this study, we extended our studies to determine whether the Wnt/beta-catenin signaling pathway inhibited death receptor-mediated apoptosis in HNSCC cells. We found that Wnt/beta-catenin inhibited not only tumor necrosis factor (TNF)/c-Myc-mediated apoptosis, but also cell detachment-mediated apoptosis (anoikis) which is dependent on the death receptor signaling pathway. Interestingly, we also observed that the Wnt/beta-catenin signaling pathway induced HNSCC cell scattering and promoted cell invasion in the Matrigel, both of which are hallmarks for the invasive growth of HNSCC. Consistently, the over-expression of beta-catenin promoted HNSCC tumor growth in nude mice. Taken together, our results suggest that the Wnt/beta-catenin signaling pathway plays dual functions in HNSCC development: promoting both cell survival and invasive growth of HNSCC cells.     

经典Wnt信号通路与人类肿瘤

近年来,随着对肿瘤的深入研究,Wnt信号的研究也受到了高度的关注．Wnt信号通路是一条在进化上保守的信号途径,在控制胚胎发育,调节细胞生长、迁移、分化,调控正常组织重建等生命活动中发挥重要的作用,其异常活化与众多人类肿瘤的发生、发展密切相关．Wnt信号途径异常的核心是β-catenin在细胞内累积,并通过其下游途径引起特异靶基因的转录．本文着重介绍Wnt/β-catenin信号转导通路的研究进展及其与肿瘤的关系,了解该通路在肿瘤发生过程中的具体分子机制有助于为临床诊断提供依据,为早期干预治疗提供方法．     

Wnt signaling in limb organogenesis

Secreted signaling molecules of the Wnt family have been found to play a central role in controlling embryonic development of a wide range of taxa from Hydra to humans. The most extensively studied Wnt signaling pathway is the canonical Wnt pathway, which controls gene expression by stabilizing β-catenin, and regulates a multitude of developmental processes. More recently, noncanonical Wnt pathways, which are β-catenin-independent, have been found to be important developmental regulators. Understanding the mechanisms of Wnt signaling is essential for the development of novel preventive and therapeutic approaches of human diseases. Limb development is a paradigm to study the principles of Wnt signaling in various developmental contexts. In the developing vertebrate limb, Wnt signaling has been shown to have important functions during limb bud initiation, limb outgrowth, early limb patterning, and later limb morphogenesis events. This review provides a brief overview on the diversity of Wnt-dependent signaling events during embryonic development of the vertebrate limb.     

Wnt/Ca2+ signaling pathway: a brief overview

The non-canonical Wnt/Ca(2+) signaling cascade is less characterized than their canonical counterpart, the Wnt/β-catenin pathway. The non-canonical Wnt signaling pathways are diverse, defined as planer cell polarity pathway, Wnt-RAP1 signaling pathway, Wnt-Ror2 signaling pathway, Wnt-PKA pathway, Wnt-GSK3MT pathway, Wnt-aPKC pathway, Wnt-RYK pathway, Wnt-mTOR pathway, and Wnt/calcium signaling pathway. All these pathways exhibit a considerable degree of overlap between them. The Wnt/Ca(2+) signaling pathway was deciphered as a crucial mediator in development. However, now there is substantial evidence that the signaling cascade is involved in many other molecular phenomena. Many aspects of Wnt/Ca(2+) pathway are yet enigmatic. This review will give a brief overview of the fundamental and evolving concepts of the Wnt/Ca(2+) signaling pathway.     

Nuclear β-catenin localization is not sufficient for canonical Wnt signaling activation in human melanoma cell lines

In most cases, advanced stages of melanoma are practically incurable due to high metastatic potential of tumor cells. Multiple observations support the idea that aberrations in the Wnt signaling pathway play a significant role in melanoma development and progression. Canonical Wnt signaling activation results in stabilization and accumulation of the major effector molecule called & gb-catenin. Mutations promoting & gb-catenin stabilization and, thereby, activation of canonical Wnt signaling pathway are frequently found in different cancers but rarely observed in melanomas. Nevertheless, & gb-catenin nuclear and cytoplasmic accumulation is the feature of many human melanoma cell lines and original tumors. That is why the aim of the investigation was to elucidate the relation between & gb-catenin intracellular localization and activity status of Wnt signaling pathway in human melanoma cell lines. Ten human melanoma cell lines were characterized on the basis of the following parameters: canonical Wnt ligand expression, intracellular & gb-catenin localization and activity status of canonical Wnt signaling pathway. Here, it has been demonstrated that nuclear localization of & gb-catenin does not always correspond to active status of canonical Wnt signaling pathway. Moreover, in the majority of cell lines with nuclear & gb-catenin, canonical Wnt signaling cannot be activated by exogenous expression of an appropriate ligand. Human melanoma cell lines differ in activity of canonical Wnt signaling pathway as well as in mechanisms of its regulation. Therefore, pathway-targeted potential antineoplastic therapy requires the formation of a & ldmolecular pattern of cancer” for localization of the defect in Wnt signaling cascade in each case.     

Wnt signaling and skeletal development

Wnt proteins are a family of secreted proteins that regulate many aspects of cellular functions. The discovery that mutations in low-density lipoprotein receptor-related protein 5, a putative Wnt coreceptor, could positively and negatively affect bone mass in humans generated an enormous amount of interest in the possible role of the Wnt signaling pathway in skeletal biology. Over the last decade, considerable progress has been made in determining the role of the canonical Wnt signaling pathway in various aspects of skeletal development. Furthermore, recent evidence indicates the important role of non-canonical Wnt signaling in skeletal development. In this review we discuss the current understanding of the role of Wnt signaling in chondrogenesis, osteoblastogenesis, and osteoclastogenesis.     

The Wnt pathway and the roles for its antagonists, DKKS, in angiogenesis

The Wnt signaling pathway is involved in a wide range of developmental and physiological processes, such as cell fate specification, tissue morphogenesis, and homeostasis. Thus, its dysregulation has been found in multiple diseases, including some cardiovascular disorders. The loss or gain of function of Wnt pathway components results in abnormal vascular development and angiogenesis. Further study has revealed that Wnt signaling in endothelial cells appears to contribute to vascular morphogenesis and endothelial cell specification. Owing to the significance of Wnt signaling in angiogenesis, Wnt antagonists have been considered potential treatments for neovascular disorders. In line with this, members of the Dkk protein family (Dkks), well-known Wnt antagonists, have been recently found to regulate angiogenesis. This review summarizes our present knowledge of the roles of Wnt signaling and Wnt antagonists, particularly Dkks, in angiogenic regulation and explores the therapeutic potential of Wnt antagonists. ? 2012 IUBMB IUBMB Life, 64(9): 724-731, 2012.     

Noncanonical Wnt signaling through G protein-linked PKCdelta activation promotes bone formation

Wnt signaling regulates a variety of developmental processes in animals. Although the beta-catenin-dependent (canonical) pathway is known to control cell fate, a similar role for noncanonical Wnt signaling has not been established in mammals. Moreover, the intracellular cascades for noncanonical Wnt signaling remain to be elucidated. Here, we delineate a pathway in which Wnt3a signals through the Galpha(q/11) subunits of G proteins to activate phosphatidylinositol signaling and PKCdelta in the murine ST2 cells. Galpha(q/11)-PKCdelta signaling is required for Wnt3a-induced osteoblastogenesis in these cells, and PKCdelta homozygous mutant mice exhibit a deficit in embryonic bone formation. Furthermore, Wnt7b, expressed by osteogenic cells in vivo, induces osteoblast differentiation in vitro via the PKCdelta-mediated pathway; ablation of Wnt7b in skeletal progenitors results in less bone in the mouse embryo. Together, these results reveal a Wnt-dependent osteogenic mechanism, and they provide a potential target pathway for designing therapeutics to promote bone formation.     

Identification of novel triazole inhibitors of Wnt/β-catenin signaling based on the Niclosamide chemotype

Dysregulation of the Wnt signaling pathway is an underlying mechanism in multiple diseases, particularly in cancer. Until recently, identifying agents that target this pathway has been difficult and as a result, no approved drugs exist that specifically target this pathway. We reported previously that the anthelmintic drug Niclosamide inhibits the Wnt/β-catenin signaling pathway and suppresses colorectal cancer cell growth in vitro and in vivo. In an effort to build on this finding, we sought to discover new Wnt/β-catenin inhibitors that expanded the chemotype structural diversity. Here, we asked a specific SAR question unresolved in previous SAR studies of Niclosamide’s inhibition of Wnt/β-catenin signaling to identify a new structural class of Wnt/β-catenin signaling inhibitors based on a triazole motif. Similar to Niclosamide, we found that the new triazole derivatives internalized Frizzled-1 GFP receptors, inhibited Wnt/β-catenin signaling in the TOPflash assay and reduced Wnt/β-catenin target gene levels in CRC cells harboring mutations in the Wnt pathway. Moreover, in pilot SAR studies, we found the Wnt/β-catenin SAR trends in the anilide region were generally similar between the two chemical classes of inhibitors. Overall, these studies demonstrate the ability to use the SAR of the Niclosamide salicylanilide chemical class to expand the structural diversity of Wnt/β-catenin inhibitors.