ICG-001

The transcription factor β-catenin is able to induce tolerogenic/anti-inflammatory features in different types of dendritic cells (DCs). Monocyte-derived dendritic cells (moDCs) have been widely used in dendritic cell-based cancer therapy, but so far with limited clinical efficacy. We wanted to investigate the hypothesis that aberrant differentiation or induction of dual pro- and anti-inflammatory features may be β-catenin dependent in moDCs. β-catenin was detectable in both immature and lipopolysaccharide (LPS)-stimulated DCs...

Epidermal growth factor receptor (EGFR) is a major driver of head and neck cancer, a devastating malignancy with a major sub-site in the oral cavity manifesting as oral squamous cell carcinoma (OSCC). EGFR is a glycoprotein receptor tyrosine kinase (RTK) whose activity is upregulated in >80% OSCC. Current anti-EGFR therapy relies on the use of cetuximab, a monoclonal antibody against EGFR, although it has had only a limited response in patients. Here, we uncover a novel mechanism regulating EGFR activity, identifying a role of the nuclear branch of the Wnt/β-catenin signaling pathway, the β-catenin/CBP axis, in control of post-translational modification of N-glycans on the EGFR...

Chronic kidney disease (CKD) has a high prevalence worldwide. Renal fibrosis is the common pathological feature in various types of CKD. However, the underlying mechanisms are not determined. Here, we adopted different CKD mouse models and cultured human proximal tubular cell line (HKC-8) to examine the expression of C-X-C motif chemokine receptor 4 (CXCR4) and β-catenin signalling, as well as their relationship in renal fibrosis. In CKD mice and humans with a variety of nephropathies, CXCR4 was dramatically up-regulated in tubules, with a concomitant activation of β-catenin...

The aim of this study was to investigate whether the Notch pathway is modulated in response to the downregulation of the Wnt/Β-catenin system in corpora lutea (CLs) from superovulated rats. To this end, we analyzed the effect of in vitro CL Wnt/Β-catenin inhibition on the expression of Notch members and on luteal function. Mechanically isolated rat CLs were cultured with ICG-001, a Wnt/B-catenin inhibitor. In this system, Wnt/B-catenin inhibition reduced progesterone production and decreased StAR protein levels...

Renal fibrosis compromises kidney function, and it is a risk factor for chronic kidney disease (CKD). CKD ultimately progresses to end-stage kidney disease that can be cured only by kidney transplantation. Owing to the increasing number of CKD patients, effective treatment strategies are urgently required for renal fibrosis. TGF-β is a well-established fibrogenic factor that signals through SMAD2/3 signaling pathway. It was shown that there is a cross-talk between TGF-β/SMAD and WNT/β-catenin signaling pathways in renal tubular epithelial cells, and that a WNT/β-catenin inhibitor, ICG-001, ameliorates TGF-β1induced renal fibrosis...

Four-and-a-half LIM domains protein 2 (FHL2) has been proposed involving in β-catenin activity. We previously reported that FHL2 mediates TGF-β1-induced tubular epithelial-to-mesenchymal transition through activating Wnt/β-catenin signaling. However, the potential role and mechanism for FHL2 in TGF-β1-induced fibroblast activation and kidney fibrosis remains unknown. Here, we initially observed higher levels of FHL2 expression in fibrotic kidneys from both patients and mice, especially in α-smooth muscle actin (α-SMA)-positive cells in the interstitium...

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological disorder that results from the clonal transformation of T-cell precursors. Phosphatidylinositol 3-kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) and canonical Wnt/β-catenin signaling pathways play a crucial role in T-cell development and in self-renewal of healthy and leukemic stem cells. Notably, β-catenin is a transcriptional regulator of several genes involved in cancer cell proliferation and survival. In this way, aberrations of components belonging to the aforementioned networks contribute to T-ALL pathogenesis...

Endometriosis exhibits unique characteristics, such as fibrosis, resistance to apoptosis, and promotion of cell proliferation; however, its pathophysiology is not fully understood. Recurrence rates after treatment are high, and the progression risk continues until menopause; hence, more effective therapy for endometriosis is needed. CREB-binding protein (CBP)/β-catenin signaling inhibitors have demonstrated antifibrogenetic effects in liver, lung, and skin diseases. The present study evaluated the effects of two CBP/β-catenin signaling inhibitors, ICG-001 and C-82, on the progression of endometriosis using endometriotic cyst stromal cells from the ovary and normal endometrial stromal cells from the uterus...

Triple-negative breast cancers (TNBCs), which lack specific targeted therapy options, evolve into highly chemo-resistant tumors that metastasize to multiple organs simultaneously. We have previously shown that TNBCs maintain an activated WNT10B-driven network that drives metastasis. Pharmacologic inhibition by ICG-001 decreases β-catenin-mediated proliferation of multiple TNBC cell lines and TNBC patient-derived xenograft (PDX)-derived cell lines. In vitro, ICG-001 was effective in combination with the conventional cytotoxic chemotherapeutics, cisplatin and doxorubicin, to decrease the proliferation of MDA-MB-231 cells...

We have previously shown that activation of (pro)renin receptor (PRR) induces ENaC activity in cultured collecting duct (CD) cells. Here we examined the role of soluble PRR (sPRR), the cleavage product of PRR in ENaC regulation and further tested its relevance to aldosterone (Aldo) signaling. In cultured mpkCCD cells, administration of a recombinant histidine-tagged sPRR, sPRR-His at 10 nM within minutes induced a significant and transient increase in the amiloride-sensitive short circuit current (Isc) as assessed by using Ussing chamber technique...

Peri-prosthetic osteolysis (PPO) often generates after total joint arthroplasty, which can bring implant failure and following revision surgery. Wear debris shed from prostheses strongly enhances bone resorption and attenuates bone formation in osteolytic process. We previously proved that suppression of protein phosphatase 2A (PP2A), a major serine-threonine phosphatase, inhibited wear-debris-induced osteoclastogenesis and alleviated local osteolysis. Whether PP2A inhibition facilitates osteoblastogenesis and bone formation in the osteolytic sites remains unclear...

Background: During osteoporosis, bone mesenchymal stem cells (BMSCs) lineage commitment shifts to adipocytes, causing fat accumulation and bone loss in the skeleton. Seeking drugs that could reverse the adipocyte fate determination of BMSCs is critical for osteoporosis therapy. As a traditional Chinese medicine, Rhizoma Curculiginis (Xianmao) has been used to treat bone diseases and promote bone healing, while the effective constituent of it and the underlying mechanisms are unknown. Objectives: The aim of this study is to unveil the role of orcinol glucoside (OG), one constituent of Rhizoma Curculiginis, in osteoporosis and BMSCs lineage commitment and to explore the underlying mechanisms...

Normal long-term repopulating somatic stem cells (SSCs) preferentially divide asymmetrically, with one daughter cell remaining in the niche and the other going on to be a transient amplifying cell required for generating new tissue in homeostatic maintenance and repair processes, whereas cancer stem cells (CSCs) favor symmetric divisions. We have previously proposed that differential β-catenin modulation of transcriptional activity via selective interaction with either the Kat3 coactivator CBP or its closely related paralog p300, regulates symmetric versus asymmetric division in SSCs and CSCs...

The early recurrence of hepatocellular carcinoma (HCC) is the main obstacle for long-term survival of patients. Wnt/β-catenin signaling has been involved in the development and progression of HCC. However, the molecular changes that link Wnt/β-catenin activation and HCC early recurrence remain poorly understood. Here we identified AKIP1 as a binding partner of β-catenin. AKIP1 interacted with and sustained β-catenin in the nuclear by blocking its interaction with adenomatous polyposis coli protein (APC)...

M2-polarized tumor-associated macrophages (M2-TAMs) infiltrating the tumor microenvironment contribute to hepatocellular carcinoma (HCC) progression. It was reported that cancer cells undergoing EMT will acquire stemness characteristics. Here, the HCC SMMC-7721 cell line was co-cultured with M2-TAMs polarized from THP-1 cells in vitro. In in vivo studies, we used nude mice subcutaneous tumor model to test whether the growth of the tumor was affected by M2-TAMs. Subsequently, EMT, stemness and Wnt/β-catenin pathway related markers were detected in cells and subcutaneous tumor tissues...

Liposarcoma is the most common soft tissue sarcoma. Molecularly targeted therapeutics have had limited efficacy in liposarcomas, in part because of inadequate knowledge of the complex molecular alterations in these tumors. Our recent study revealed the tumor suppressive function of miR-193b in liposarcoma. Considering the biological and clinical heterogeneity of liposarcoma, here, we confirmed the under-expression of miR-193b in additional patient liposarcoma samples and cell lines. Based on STRING analysis of protein-protein interactions among the reported putative miR-193b targets, we validated three: PDGFRβ, SMAD4, and YAP1, belonging to strongly interacting pathways (focal adhesion, TGFβ, and Hippo, respectively)...

OBJECTIVE: To explore the influence of micro ribonucleic acid (miR)-154 on myocardial apoptosis in rats with acute myocardial infarction (AMI), and to analyze whether Wnt/β-catenin signaling pathway was involved in the regulation. MATERIALS AND METHODS: The Sprague-Dawley (SD) rat model of AMI was established via ligation of left anterior descending artery. Rats were randomly divided into model group (M group, n=12) and ICG-001 intervention group (I group, n=12)...

Activation of the renin-angiotensin system (RAS) plays a pivotal role in mediating hypertension, chronic kidney and cardiovascular diseases. As Wnt/β-catenin regulates multiple RAS genes, we speculated that this developmental signaling pathway might also participate in blood pressure (BP) regulation. To test this, we utilized two rat models of experimental hypertension: chronic angiotensin II infusion and remnant kidney after 5/6 nephrectomy. Inhibition of Wnt/β-catenin by ICG-001 blunted angiotensin II-induced hypertension...

Epidermal growth factor-like protein 6 (EGFL6) serves as an exocrine protein promoting proliferation and migration during carcinogenesis in ovarian cancer. However, its function and mechanisms in colorectal cancer (CRC) have not been completely explored. To investigate the role of EGFL6 in CRC cell growth, in vitro CCK8, colony formation assays, flow cytometric analysis of the cell cycle and apoptosis, and an in vivo tumor xenograft model were utilized. Additionally, Western blotting and luciferase reporter assays were used to investigate the underlying mechanisms of EGFL6 function on the WNT/β-catenin signaling pathway...

Background: Renal fibrosis is a key pathological feature and final common pathway leading to end-stage kidney failure in many chronic kidney diseases. Myofibroblast is the master player in renal fibrosis. However, myofibroblasts are heterogeneous. Recent studies show that bone marrow-derived macrophages transform into myofibroblasts by transforming growth factor (TGF)-β-induced macrophage-myofibroblast transition (MMT) in renal fibrosis. Methods: TGF-β signaling was redirected by inhibition of β-catenin/T-cell factor (TCF) to increase β-catenin/Foxo in bone marrow-derived macrophages...