Toward Defining the Functional Relevance of Wnt Signaling in Osteoclasts in Multiple Myeloma.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3422-3422
Author(s):  
Ya-Wei Qiang ◽  
Yu Chen ◽  
Nathan Brown ◽  
Rohit P. Ojha ◽  
Stuart Rudikoff ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Wnt Signaling ◽  
Wnt Signaling Pathway ◽  
Specific Inhibitor ◽  
Raw264.7 Cells ◽  
Beta Catenin ◽  
Direct Role ◽  
Myeloma Bone Disease ◽  
High Level

Abstract Disruption of Wnt signaling is thought to play a central role in the development of myeloma bone disease. Although Wnt signaling in osteoblasts (OB) is essential for their differentiation and Wnt signaling in OB indirectly regulates osteoclast (OC) development through the regulation of both OPG and RANKL, little is known about the direct role of Wnt signaling in osteoclastogenesis. In this study, we sought to characterize the Wnt signaling pathway and its functional role in OC formation using the macrophage cell line Raw 264.7, which can be induced to differentiate into OC, as well as human primal progenitor osteoclast cells isolated from bone marrow of normal donors and patients with MM. We first analyzed the pattern of Wnt signaling components in these cells by RT-PCR and sequence analysis. High level of expression of Wnt receptors Frizzled (Fz) Fz2, 3, 4, 5, 7, 8 and 9, and co-receptors LRP5, and LRP6, and transcription factors TCF1, TCF3, and LEF1 was observed in 10 of 10 OC cells from MM patients and 4 of 4 OC from normal donors and Raw264.7. Wnt3a conditioned medium and recombinant Wnt3a induced increased levels of total and un-phosphorylated beta-catenin in all cells. Pretreatment of OC cells with sFRP1 decreased Wnt3a induced increased beta-catenin. Pretreatment with DKK1, a specific inhibitor of the canonical Wnt pathway, blocked Wnt3a induced stabilization of beta-catenin. Additionally, the GSK3beta inhibitor lithium chloride induced stabilization of beta-catenin in OC and Raw264.7 cells in dose-dependent fashion. Wnt-3a induced TCF/LEF transcriptional activity in Raw264.7 cells transfected with TOPflash compared with Raw264.7 transfected with FOPflash, which possess mutant sequence for binding beta-catenin. These results suggest that Wnt signaling functions in primal MM OC cells, as well as OC cell lines. Finally, we sought to determine the biological function of Wnt signaling in OC cells. The results showed that Wnt-3a did not affect the proliferation and survival of OC cells, nor increased formation of TRAP positive cells. Wnt3a did not synergize with RANKL and M-CSF in induction of OC differentiation. Additional biological functional assays are underway to determine the direct role of Wnt signaling on OC. Identification of the role of Wnt signaling in osteoclastogenesis may improve our understanding of the bone lytic process in multiple myeloma.

Anti-Tumor Activity of Novel Small Molecule Wnt Signaling Inhibitor, CWP232291, In Multiple Myeloma

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3038-3038 ◽  
Author(s):  
Joo Young Cha ◽  
Ji-Eun Jung ◽  
Kwan-Hoo Lee ◽  
Isabelle Briaud ◽  
Fnu Tenzin ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Wnt Signaling ◽  
Caspase 3 ◽  
Target Genes ◽  
Plasma Cells ◽  
Wnt Signaling Pathway ◽  
Beta Catenin ◽  
Tumor Bearing ◽  
Induction Of Apoptosis ◽  
Rpmi 8226

Abstract Abstract 3038 Multiple myeloma (MM), one of the most incurable hematological malignancies in adults, is a disorder of plasma cells characterized by accumulation of clonal proliferation of malignant plasma cells in the bone marrow (BM). Overexpression of beta-catenin, the downstream effector of the canonical Wnt signaling pathway, has been reported in both MM cell lines and patient samples. Activated Wnt signaling pathway has also been reported to play a critical role in progression of MM cell proliferation, thus highlighting the need for new therapeutic approaches, particularly those targeting Wnt molecular pathway. Here we report the discovery of a novel inhibitor of Wnt signaling CWP232291, which promotes degradation of beta-catenin. CWP232291 exhibits potent growth inhibitory activity in several MM cell lines (RPMI-8226, OPM-2, NCI-H929, JJN3, and EJM) with IC50 values of 13 – 73 nM. The inhibitory activity of CWP232291 on Wnt signaling is demonstrated by reporter gene assay and by its effect in down-regulation of Wnt target genes. Using HEK293 cells, CWP232291 treatment dose dependently reduces promoter activity of TOPflash induced by Wnt-3a-Conditioned Media, at a calculated IC50 value of 273 nM. Furthermore, MM cells treated with CWP232291 show downregulated expression of Wnt target genes such as survivin by triggering degradation of beta-catenin. Treatment of these cells with CWP232291 results in activation of caspase-3 and PARP cleavage, indicating induction of apoptosis. To investigate the potential in vivo anti-tumor efficacy of CWP232291, we utilized two MM tumor bearing mice models. Daily or intermittent intravenous (i.v.) administration of CWP232291 led to significant tumor growth inhibition (TGI) in OPM-2 (50 mg/kg, qdx5: regression and 100 mg/kg, biw: 95% TGI) and RPMI-8226 (100 mg/kg, qdx5: regression and 100 mg/kg tiw: 80% TGI) xenograft model with no obvious change in body weight. The anti-tumor efficacies of CWP232291 were dose-dependent and had strong correlations with degradation of beta-catenin in the tumor samples. Potent induction of apoptosis through cleavage of Caspase-3 and PARP and significant decrease of plasma M protein levels in OPM-2 tumor bearing mice were detected as early as 2 and up to 24 hours after single i.v. administration of CWP232291. Taken together, these data clearly demonstrate the impressive anti-tumor profile of CWP232291 with a good therapeutic window and suggest a potential therapeutic application of CWP232291 for the treatment of MM. Disclosures: Cha: Choongwae Pharma Corp.: Employment. Jung:Choongwae Pharma Corp.: Employment. Lee:Choongwae Pharma Corp.: Employment. Briaud:Theriac Pharmaceutical Corp.: Employment. Tenzin:Theriac Pharmaceutical Corp.: Employment. Jung:Choongwae Pharma Corp.: Employment. Pyon:Choongwae Pharma Corp.: Employment. Lee:Choongwae Pharma Corp.: Employment. Chung:Choongwae Pharma Corp.: Employment. Lee:Choongwae Pharma Corp.: Employment. Oh:Choongwae Pharma Corp.: Employment. Jung:Choongwae Pharma Corp.: Employment. Pai:Choongwae Pharma Corp.: Employment. Emami:Theriac Pharmaceutical Corp.: Employment.

THE ROLE OF AGONISTS AND ANTAGONISTS OF THE WNT SIGNALING PATHWAY IN PATIENTS WITH ANDROGENIC ALOPECIA AND ALOPECIA AREATA

2021 ◽  
pp. 87-95
Author(s):  
Samoylova A.V. ◽  
Snimshchikova I.A. ◽  
Plotnikova M.O. ◽  
Yakushkina N.Y.
Keyword(s):  
Wnt Signaling ◽  
Hair Follicle ◽  
Signaling Pathway ◽  
Alopecia Areata ◽  
Intracellular Signaling ◽  
Wnt Signaling Pathway ◽  
Follicle Cells ◽  
Androgenic Alopecia ◽  
Active Population

Alopecia is a common pathology among the active population, which leads not only to cosmetic defects, but also to the development of somatic diseases against the background of traumatic effects and chronic stress. The pathogenetic mechanisms of hair follicle formation are complex and diverse, since numerous factors, including the components of the Wnt signaling pathway, have an effect on its morphogenesis, the study of which is the subject of this study. The search for possible early markers of the development of alopecia led to interest in the study of the main morphogenic proteins of WNT - the signaling pathway (one of the intracellular signaling pathways, which control the development of blood vessels, as well as the growth and division of hair follicle cells) sclerostin and β-catenin among patients with androgenic and alopecia areata. The article presents data on the quantitative content of β-catenin and sclerostin in the blood serum in patients with androgenic and alopecia areata. Their possible pathways of complex interaction and influence on the morphogenesis of the hair follicle and the activity of the Wnt-signaling pathway have been analyzed, and the relationship between changes in the level of morphogenic proteins of the WNT-signaling pathway with sex and the course of the disease has been described. Establishment of the prognostic role of morphogenic proteins of the WNT signaling pathway in androgenic and alopecia areata will allow not only identify the personal risk of disease progression and to determine approaches to targeted therapy, but to develop and introduce updated diagnostic screening into dermatological practice.

scholarly journals The Role of Canonical Wnt Signaling in Regulating Radioresistance

2018 ◽  
Vol 48 (2) ◽  
pp. 419-432 ◽  
Author(s):  
Yuanyuan Zhao ◽  
Leilei Tao ◽  
Jun Yi ◽  
Haizhu Song ◽  
Longbang Chen
Keyword(s):  
Wnt Signaling ◽  
Cancer Progression ◽  
Wnt Signaling Pathway ◽  
Growth Factor Receptor ◽  
Cancer Resistance ◽  
Canonical Wnt Signaling ◽  
Damage Repair ◽  
Epidermal Growth ◽  
Canonical Wnt

Radioresistance is a major obstacle in radiotherapy for cancer, and strategies are needed to overcome this problem. Currently, radiotherapy combined with targeted therapy such as inhibitors of phosphoinosotide 3-kinase/Akt and epidermal growth factor receptor signaling have become the focus of studies on radiosensitization. Apart from these two signaling pathways, which promote radioresistance, deregulation of Wnt signaling is also associated with the radioresistance of multiple cancers. Wnts, as important messengers in the tumor microenvironment, are involved in cancer progression mainly via canonical Wnt signaling. Their role in promoting DNA damage repair and inhibiting apoptosis facilitates cancer resistance to radiation. Thus, it seems reasonable to target Wnt signaling as a method for overcoming radioresistance. Many small-molecule inhibitors that target the Wnt signaling pathway have been identified and shown to promote radiosensitization. Therefore, a Wnt signaling inhibitor may help to overcome radioresistance in cancer therapy.

A Wnt signaling pathway controls hox gene expression and neuroblast migration in C. elegans

Development ◽  
1999 ◽  
Vol 126 (1) ◽  
pp. 37-49 ◽  
Author(s):  
J.N. Maloof ◽  
J. Whangbo ◽  
J.M. Harris ◽  
G.D. Jongeward ◽  
C. Kenyon
Keyword(s):  
Gene Expression ◽  
Wnt Signaling ◽  
Wnt Pathway ◽  
Hox Genes ◽  
Wnt Signaling Pathway ◽  
Beta Catenin ◽  
Hox Gene ◽  
C Elegans ◽  
Neuroblast Migration ◽  
Pathway Gene

The specification of body pattern along the anteroposterior (A/P) body axis is achieved largely by the actions of conserved clusters of Hox genes. Limiting expression of these genes to localized regional domains and controlling the precise patterns of expression within those domains is critically important for normal patterning. Here we report that egl-20, a C. elegans gene required to activate expression of the Hox gene mab-5 in the migratory neuroblast QL, encodes a member of the Wnt family of secreted glycoproteins. We have found that a second Wnt pathway gene, bar-1, which encodes a beta-catenin/Armadillo-like protein, is also required for activation of mab-5 expression in QL. In addition, we describe the gene pry-1, which is required to limit expression of the Hox genes lin-39, mab-5 and egl-5 to their correct local domains. We find that egl-20, pry-1 and bar-1 all function in a linear genetic pathway with conserved Wnt signaling components, suggesting that a conserved Wnt pathway activates expression of mab-5 in the migratory neuroblast QL. Moreover, we find that members of this Wnt signaling system play a major role in both the general and fine-scale control of Hox gene expression in other cell types along the A/P axis.

scholarly journals Secreted frizzled-related protein 2: a key player in noncanonical Wnt signaling and tumor angiogenesis

2020 ◽  
Author(s):  
Karlijn van Loon ◽  
Elisabeth J. M. Huijbers ◽  
Arjan W. Griffioen
Keyword(s):  
Wnt Signaling ◽  
Tumor Angiogenesis ◽  
Wnt Signaling Pathway ◽  
Tumor Vasculature ◽  
Great Promise ◽  
Cancer Therapies ◽  
Rich Domain ◽  
Metastatic Setting ◽  
Angiogenic Effect

Abstract Secreted frizzled-related proteins (SFRP) are glycoproteins containing a so-called frizzled-like cysteine-rich domain. This domain enables them to bind to Wnt ligands or frizzled (FzD) receptors, making potent regulators of Wnt signaling. As Wnt signaling is often altered in cancer, it is not surprising that Wnt regulators such as SFRP proteins are often differentially expressed in the tumor microenvironment, both in a metastatic and non-metastatic setting. Indeed, SFRP2 is shown to be specifically upregulated in the tumor vasculature of several types of cancer. Several studies investigated the functional role of SFRP2 in the tumor vasculature, showing that SFRP2 binds to FzD receptors on the surface of tumor endothelial cells. This activates downstream Wnt signaling and which is, thereby, stimulating angiogenesis. Interestingly, not the well-known canonical Wnt signaling pathway, but the noncanonical Wnt/Ca2+ pathway seems to be a key player in this event. In tumor models, the pro-angiogenic effect of SFRP2 could be counteracted by antibodies targeting SFRP2, without the occurrence of toxicity. Since tumor angiogenesis is an important process in tumorigenesis and metastasis formation, specific tumor endothelial markers such as SFRP2 show great promise as targets for anti-cancer therapies. This review discusses the role of SFRP2 in noncanonical Wnt signaling and tumor angiogenesis, and highlights its potential as anti-angiogenic therapeutic target in cancer.

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