WNT/β-Catenin Signaling Inhibitor IC-2 Suppresses Sphere Formation and Sensitizes Colorectal Cancer Cells to 5-Fluorouracil

Abstract

Abstract. Background Colorectal cancer (CRC) is one of the most common cancer types in the world and carries the second highest mortality rate (1). Although initial events in CRC are relatively well studied and treatment for early-stage disease has significantly improved over the past decades, the mechanisms of metastasis and relapse, which are the main causes of death, remain poorly characterized (2). Currently, no effective therapy is available for advanced or metastatic disease and the survival rate at 5 years of follow-up is approximately 50% (3). Thus, a novel therapeutic strategy is urgently required for improving the clinical outcome of CRC.Recent studies suggest that a small subpopulation of cells, so-called cancer stem cells (CSCs), possess high tumorigenicity (4-6). CSCs have the unique features of selfrenewal and asymmetrical division, and are resistant to radio-and chemotherapy (7,8). The CSCs remaining after conventional therapies may promote the high metastasis and relapse of CRC. Therefore, suppression of CSCs is considered a promising approach to improve therapeutic effects on many types of cancers including CRC.Most CRCs carry somatic mutations in one of two genes, adenomatous polyposis coli (APC) and β-catenin (CTNNB1) (9-11). Defect of these genes activates the canonical winglesstype MMTV integration site family (WNT)/β-catenin signaling pathway. It has been shown that the WNT/β-catenin signaling regulates expression levels of CSC marker genes and is essential for maintenance of the undifferentiated status and self-renewal capability of CSCs (12-14). Since we recently developed a derivative of a WNT/β-catenin signaling inhibitor, IC-2, which efficiently suppresses WNT/β-catenin transcriptional activity and induces hepatic differentiation of human mesenchymal stem cells (MSCs) (15, 16), we explored its effect on colorectal cancer cells. Materials and MethodsSmall molecular compounds. We recently developed WNT/β-catenin signaling inhibitors. IC-2, a derivative of ICG-001, efficiently represses WNT/β-catenin signaling and most effectively induces hepatic differentiation of human MSCs (16). The DNA/RNA synthesis inhibitor, 5-fluorouracil (5-FU) was purchased from Nacalai tesque inc. (Kyoto, Japan). The compounds were 4085

Dysregulated Phosphorylation of p53, Autophagy and Stemness Attributes the Mutant p53 Harboring Colon Cancer Cells Impaired Sensitivity to Oxaliplatin

“…CD44 being a Wnt/β-catenin target gene, along with other studies indicating the link between Wnt/β-catenin signaling pathway, CSC and chemoresistance ( 35 , 36 ), we determined the expression of β-catenin. In HCT 116 cells, OX treatment was found to inhibit the accumulation of β-catenin ( Figures 6E,F ) while in HT 29 cells a significant accumulation of β-catenin was observed with OX treatment ( Figures 6G,H ).…”

“…For instance, Urushibara et al ( 35 ) tried to inhibit the expression of CSC proteins using a Wnt/β-catenin signaling inhibitor “IC-2” and found enhanced cytotoxicity to the drug 5-FU (fluorouracil) by colon cancer cells. Another study by Chen et al ( 36 ) has shown that suppression of Axin2 (a negative feedback regulator of Wnt/β-catenin signaling) by micro RNA: miR-103/107 enhanced chemoresistance of colon cancer cells via inducing stemness.…”

IC-2 Suppresses Proliferation and Induces Apoptosis of Bladder Cancer Cells via the Wnt/β-Catenin Pathway

“…In vivo , Western blot and immunohistochemistry assay showed that expression of β-catenin protein was decreased mice treated with IC-2 (5 mg/kg) and the tumor volume was also reduced, suggesting that IC-2 inhibits bladder cancer in vivo . In CRC cells, IC-2 reduced Wnt/β-catenin transcriptional activity and decreased the expression levels of cancer stem cell marker proteins [ 26 ].…”

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

“…Diallyl trisulfide inhibits CRC stem cells by promoting the expression of GSK-3β and inhibiting the expression of β-catenin and CRC stem cell markers in CRC stem cells ( 49 ). IC-2, a derivative of Wnt/β-catenin signaling inhibitor ICG-001, inhibits the expression of CRC stem cell marker proteins, as well as the sphere formation activity of CRC cells ( 102 ). ICG-001 promotes cell differentiation, suppresses cell proliferation, and induces apoptosis via binding to CREB-binding protein in CRC cells ( 103 , 104 ), suggesting that IC-2 may also bind to this protein to suppress the sphere formation of CRC cells via inhibition of the expression of CRC stem cell markers.…”