xav939 and Colonic-Neoplasms

Dysregulation of the Wnt/β-catenin signaling pathway has been widely recognized as a pathogenic mechanism for colorectal cancer (CRC). Although numerous Wnt inhibitors have been developed, they commonly suffer from toxicity and unintended effects. Moreover, concerns have been raised in targeting this pathway because of its critical roles in maintaining stem cells and regenerating tissues and organs. On the basis of the anthelmintic drug pyrvinium and previous lead FX1128, we have developed a compound YW2065 (

Topics: AMP-Activated Protein Kinases; Animals; Antineoplastic Agents; Apoptosis; beta Catenin; Cell Proliferation; Colonic Neoplasms; Female; Gene Expression Regulation, Neoplastic; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Nude; Phosphorylation; Pyrazoles; Tumor Cells, Cultured; Wnt Signaling Pathway; Xenograft Model Antitumor Assays

Caudal-related homeobox transcription factor 2 (CDX2), an intestine-specific nuclear transcription factor, has been strongly implicated in the tumourigenesis of various human cancers. However, the functional role of CDX2 in the development and progression of colorectal cancer (CRC) is not well known. In this study, CDX2 knockdown in colon cancer cells promoted cell proliferation in vitro, accelerated tumor formation in vivo, and induced a cell cycle transition from G0/G1 to S phase, whereas CDX2 overexpression inhibited cell proliferation. TOP/FOP-Flash reporter assay showed that CDX2 knockdown or CDX2 overexpression significantly increased or decreased Wnt signaling activity. Western blot assay showed that downstream targets of Wnt signaling, including β-catenin, cyclin D1 and c-myc, were up-regulated or down-regulated in CDX2-knockdown or CDX2-overexpressing colon cancer cells. In addition, suppression of Wnt signaling by XAV-939 led to a marked suppression of the cell proliferation enhanced by CDX2 knockdown, whereas activation of this signaling by CHIR-99021 significantly enhanced the cell proliferation inhibited by CDX2 overexpression. Dual-luciferase reporter and quantitative chromatin immunoprecipitation (qChIP) assays further confirmed that CDX2 transcriptionally activates glycogen synthase kinase-3β (GSK-3β) and axis inhibition protein 2 (Axin2) expression by directly binding to the promoter of GSK-3β and the upstream enhancer of Axin2. In conclusion, these results indicated that CDX2 inhibits the proliferation and tumor formation of colon cancer cells by suppressing Wnt/β-catenin signaling.

Topics: Animals; Axin Protein; beta Catenin; Caco-2 Cells; Carcinogenesis; CDX2 Transcription Factor; Cell Cycle Checkpoints; Cell Proliferation; Colonic Neoplasms; Cyclin D1; Female; Gene Knockdown Techniques; Glycogen Synthase Kinase 3 beta; Heterocyclic Compounds, 3-Ring; Heterografts; HT29 Cells; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Proto-Oncogene Proteins c-myc; Pyridines; Pyrimidines; Transfection; Tumor Burden; Wnt Proteins; Wnt Signaling Pathway

Aberrant Wnt signaling pathway is associated with a wide array of tumor types and plays an important role in the drug resistance of cancer stem cells (CSCs). To explore the effects and mechanism of WNT signaling pathway inhibitor XAV939 on drug resistance in colon cancer cells, the colon cancer cells SW480 and SW620 were treated with 5-fluorouracil (5-FU)/cisplatin (DDP) alone or combined with XAV939. Cell cycle distribution, apoptosis level and the percentage of CD133+ cells were detected by flow cytometry. The protein expression of Axin, β-catenin, EpCAM, TERT and DCAMKL-1 was detected by western blotting. XAV939 upregulated Axin , decreased the total and nuclei of β-catenin in SW480 and SW620 cells. Furthermore, XAV939 significantly downregulated the CSC markers EpCAM, TERT and DCAMKL-1 in SW480 cells, as well as EpCAM in SW620 cells. No significant difference was found in the apoptosis of SW480 and SW620 cells with XAV939 treatment, but XAV939 significantly increased apoptosis induced by 5-FU/DDP in SW480 cells, whereas, the effects were slight in SW620 cells. Collectively, we show for the first time that the WNT signaling pathway inhibitor XAV939 was able to significantly increase the apoptosis induced by 5-FU/DDP, accompanied by the protein expression level alternation of β-catenin, Axin and CSC markers in colon cancer cells. Axin, an important component of Wnt/β-catenin signaling pathway could be a potential molecular target for reversing multidrug resistance in colon cancer.

Topics: Apoptosis; Axin Protein; beta Catenin; Cell Line, Tumor; Cell Proliferation; Cisplatin; Colonic Neoplasms; Drug Resistance, Neoplasm; Fluorouracil; Gene Expression Regulation, Neoplastic; Heterocyclic Compounds, 3-Ring; Humans; Neoplastic Stem Cells; Tankyrases; Wnt Signaling Pathway

The constitutive activation of Wnt/β-catenin signaling plays a central role in colon cancer. MiR-145 was earlier identified as one of the microRNAs (miRNAs) down-regulated in colon cancer cells. However, the role of miR-145 in the Wnt/β-catenin signaling pathway is poorly understood. Here, we demonstrated that miR-145 played a pivotal role in the Wnt/β-catenin signaling pathway by perturbing the intracellular translocation of β-catenin in human colon cancer cells. The ectopic expression of miR-145 inhibited the growth of DLD-1 cells by disturbing β-catenin translocation into the nucleus, thereby leading to the down-regulation of LEF/TCF transcriptional target genes c-Myc and CyclinD1. We further demonstrated that miR-145 directly targeted catenin δ-1, contributing to the aberrant translocation of β-catenin through impaired nuclear shuttling with p21-activated kinase 4 (PAK4). These findings uncover a novel role of miR-145 in modulating intracellular translocation of β-catenin on Wnt/β-catenin signaling pathway.

Topics: Active Transport, Cell Nucleus; beta Catenin; Catenins; Cell Line, Tumor; Cell Movement; Cell Proliferation; Colonic Neoplasms; Cyclin D1; Delta Catenin; Down-Regulation; Genes, myc; Heterocyclic Compounds, 3-Ring; Humans; MicroRNAs; p21-Activated Kinases; Protein Transport; RNA Interference; RNA, Small Interfering; Tankyrases; Wnt Proteins; Wnt Signaling Pathway