| Abstract [eng] |
The intrinsic or acquired drug resistance is one of the culprits leading to the failure of colorectal cancer (CRC) treatment. In this study, the importance of autophagy and Wnt/β-catenin, Notch1 signaling pathways for the response of human CRC cells HCT116 and chemoresistant sublines HCT116/FU (generated by cell cultivation with 5-fluorouracil, hereafter 5-FU), HCT116/OXA (generated by cell cultivation with oxaliplatin, hereafter OxaPt) to cytotoxic treatment was investigated. In monolayer cell culture (2D) HCT116/FU cells were sensitive to mTHPC photodynamic treatment which inhibited autophagic flux, both in HCT116 and HCT116/FU cells. In HCT116, HCT116/FU and HCT116/OXA cell lines, 5-FU diminished the autophagic flux, while OxaPt increased it. The downregulation of autophagy protein ATG7 had no impact on 5-FU cytotoxicity and weakened the effects of OxaPt. 5-FU treatment decreased Wnt/β-catenin and Notch1 signaling in all tested cell lines, while OxaPt – decreased it only in OxaPt-sensitive cells. The inhibition of Wnt/β-catenin and Notch signaling sensitized chemoresistant cell spheroids to 5-FU. While the inhibition of Notch signaling augmented cell the resistance to OxaPt in all cell lines grown both in 2D and spheroid culture. |
