Numerical modelling of WNT/fi-catenin signal pathway in characterization of EMT of colorectal carcinoma cell lines after treatment with Pt(IV) complexes

Background and objective: Colorectal cancer (CRC) is at the top of the most common cancer types in the world, with significant mortality rates among both men and women. Deregulation of Wnt/ fi-catenin pathway and cell-cell junctions' components, acquisition of invasive phenotype, epithelial-mesenchymal transition (EMT) and invasion are important for development and progression of colorectal cancer. Nu-merical simulation presents method for estimation of the Wnt pathway via its individual components in cells, thus providing information about EMT, migratory and invasive potential. By using this numerical model, the effectiveness of treatment in EMT suppression can be assessed. Furthermore, the model can be adapted to every cell type, application time or duration of treatment can be also modified. Methods: We characterized colorectal cancer (CRC) cell lines (HCT-116, SW-480) from the aspect of EMT, via markers fi-catenin and E-cadherin using numerical modeling. To confirm the numerical model, cells were treated with sublethal concentrations of platinum(IV) complexes and their ligands. We confirmed fi- catenin regulated expression of mesenchymal markers: N-cadherin, Vimentin and MMP-9, and decreased E-cadherin expression. Treatment-induced changes were determined in the protein expression of tested markers and results showed cell-specific responses. Molecular docking was performed to investigate exact effects of treatments on E-cadherin and fi-catenin in cell-cell junctions and individually in tested cells. Results: The application of the numerical model via fi-catenin and E-cadherin (experimentally measured), is largely valid for the categorization of EMT progression in cells. This numerical modeling better charac-terizes cells with single cell migration, higher expression of mesenchymal markers, and advanced mes-enchymal phenotype like HCT-116 cell line. The model was validated for the treatments and results show HCT-116 cells as more sensitive to applied compounds, among which ligands were more potent in re-ducing migration and invasiveness. Anti-migratory/invasive effects were due to increased E-cadherin, cy-toplasmic fi-catenin expression and suppressed mesenchymal markers. In silico methods showed higher affinity of tested chemicals towards free fi-catenin, which is the key for regulation of migratory/invasive potential. Conclusions: Our study shows that, no matter individual properties of cell lines and EMT degree, de novo formation of intercellular junctions stands in the basis of anti-migratory/invasive process. (c) 2022 Elsevier B.V. All rights reserved.

Automated summary

This study categorized the progression of epithelial-mesenchymal transition (EMT) in colorectal cancer using numerical modeling and experimental validation. The effectiveness of treatment in EMT suppression was assessed, and the sensitivity and anti-migratory/invasive effects varied between different cell types and treatments.