fh535 has been researched along with Colonic-Neoplasms* in 2 studies
2 other study(ies) available for fh535 and Colonic-Neoplasms
Article | Year |
---|---|
An Underlying Mechanism of Dual Wnt Inhibition and AMPK Activation: Mitochondrial Uncouplers Masquerading as Wnt Inhibitors.
The importance of upregulated Wnt signaling in colorectal cancers led to efforts to develop inhibitors that target β-catenin in this pathway. We now report that several "Wnt inhibitors" that allegedly target β-catenin actually function as mitochondrial proton uncouplers that independently activate AMPK and concomitantly inhibit Wnt signaling. As expected for a process in which mitochondrial uncoupling diminishes ATP production, a mitochondrial proton uncoupler, FCCP, and a glucose metabolic inhibitor, 2-DG, activated AMPK and inhibited Wnt signaling. Also consistent with these findings, a well-known "Wnt inhibitor", FH535, functioned as a proton uncoupler, and in support of this finding, the Topics: AMP-Activated Protein Kinases; Animals; beta Catenin; Brain; Colonic Neoplasms; Energy Metabolism; Enzyme Activation; Enzyme Activators; Gene Expression Regulation, Neoplastic; Humans; Hydrocarbons, Fluorinated; Mitochondria; Oxygen Consumption; Sulfonamides; Tumor Cells, Cultured; Urea; Wnt Proteins | 2019 |
Expression of μ-protocadherin is negatively regulated by the activation of the β-catenin signaling pathway in normal and cancer colorectal enterocytes.
Mu-protocadherin (MUCDHL) is an adhesion molecule predominantly expressed by colorectal epithelial cells which is markedly downregulated upon malignant transformation. Notably, treatment of colorectal cancer (CRC) cells with mesalazine lead to increased expression of MUCDHL, and is associated with sequestration of β-catenin on the plasma membrane and inhibition of its transcriptional activity. To better characterize the causal relationship between β-catenin and MUCDHL expression, we performed various experiments in which CRC cell lines and normal colonic organoids were subjected to culture conditions inhibiting (FH535 treatment, transcription factor 7-like 2 siRNA inactivation, Wnt withdrawal) or stimulating (LiCl treatment) β-catenin activity. We show here that expression of MUCDHL is negatively regulated by functional activation of the β-catenin signaling pathway. This finding was observed in cell culture systems representing conditions of physiological stimulation and upon constitutive activation of β-catenin in CRC. The ability of MUCDHL to sequester and inhibit β-catenin appears to provide a positive feedback enforcing the effect of β-catenin inhibitors rather than serving as the primary mechanism responsible for β-catenin inhibition. Moreover, MUCDHL might have a role as biomarker in the development of CRC chemoprevention drugs endowed with β-catenin inhibitory activity. Topics: beta Catenin; Caco-2 Cells; Cadherin Related Proteins; Cadherins; Colonic Neoplasms; Enterocytes; Feedback, Physiological; Gene Expression Regulation, Neoplastic; HCT116 Cells; Humans; Lithium Chloride; Primary Cell Culture; RNA, Small Interfering; Sulfonamides; Tissue Culture Techniques; Transcription Factor 7-Like 2 Protein; Wnt Signaling Pathway | 2016 |