| Abstract [eng] |
Colorectal cancer (CRC) is the second leading cause of death worldwide. Advanced CRC is treated with a combination of the chemotherapy drugs 5-fluorouracil (5-FU) and oxaliplatin (OxaPt). One of the reasons for the high CRC mortality rate is the ability of cancer cells to adapt to the treatment. In this work, we evaluated molecular changes in resistant CRC cell sublines induced by 5-FU or OxaPt. We detected changes in the levels of cytokines, serpins and autophagy proteins in chemotherapeutic drug-resistant CRC cells and evaluated the role of autophagy in chemoresistance. We showed that cells with 5-FU-induced resistance have a higher cytokine expression compared to cells with OxaPt-induced resistance, while 5-FU or OxaPt increases cytokine expression in cells that have not adapted to the drug treatment. We also found that serpin B level is elevated in resistant sublines, whereas drug exposure increases it in parental cells and sublines with resistance induced by 5-FU. In this study, we found that the level of the autophagy protein ATG12 is elevated in the HCT116 cells with OxaPt-induced resistance and that the drugs decrease the level of ATG12 in the HCT116 line and its sublines but increase it in the SW620 line and its sublines. We have shown that ATG12 is important for the survival of CRC cells and for OxaPt resistance. We also found that the level of autophagy receptor p62 is increased in HCT116/FU cells with 5-FU-induced resistance and that the decrease in p62 protein level after drug treatment correlates with cells' drug sensitivity. We have shown that p62 promotes survival and drug resistance of the HCT116 line and its sublines. Our results suggest that p62 impacts chemoresistance by stimulating prosurvival signalling. |
