The p53 protein is a transcription factor, often labelled as the "guardian of the genome” due to its role in DNA reparation and protection from cell malignant transformation. Depending on the type (chemotherapy, UV radiation, etc.) and extent of damage to the cell, p53 can trigger DNA damage response, senescence, or if the cell is damaged irreparably, apoptosis. Because of its importance, the deregulation of p53 can lead to susceptibility to cancer, or in the case of already malignant cells, to drug resistance. In colorectal cancer (CRC) p53 mutations are found in 43% of tumours and usually are associated with advanced disease and chemoresistance to 5-fluorouracil, doxorubicin and cisplatin.
Here we show that short exposure to moderate amounts of oxaliplatin (OxaPt) leads to the downregulation of p53 in CRC cell line HCT116 expressing wild-type p53. This downregulation impairs expression of the cell cycle-arresting protein p21 and pro-apoptotic proteins BAX, FAS, DR5, PUMA, therefore rendering cells moderately resistant to OxaPt. After transfection with wild-type inducible p53 the sensitivity to OxaPt is restored. Interestingly, HCT116 cells showing high resistance to OxaPt after prolonged exposure to the drug (HCT-Oxa), harbour p53 mutations and have downregulated pro-apoptotic proteins. However, HCT-Oxa cells show no restoration of sensitivity to OxaPt after the induced expression of wild-type p53. These results suggest that the compromisation of p53 function is important for the early steps of drug resistance in CRC, but disposable for the late stage drug resistance.