Molecular patterns in colorectal cancer (CRC) cells have allowed to model responses to anti-cancer treatments. The different responses observed depend on the type of cancer, the tumor grade and the functional programme of the cancer cells. Recent studies suggest that the unfolded protein response (UPR), the autophagy and the apoptosis could be involved in treatment resistance mechanisms by interacting with the tumor microenvironment (TME). In this study, we analysed by LC-MS/MS the proteome of two representative colon adenocarcinoma epithelial cell lines from different tumor grade (CCL-233 and CCL-221) at basal state or after the UPR induction. Results showed that cell lines expressed a different proteome on about 10% of their total proteins identified, and especially on UPR, autophagy and apoptosis pathways proteins at basal state. After UPR induction, the proteome of the cells was modified with a greater adaptive response to cellular stress in CCL-221 cells where the UPR was strongly activated at basal state. Thus, we demonstrated that CRC cell lines at different tumor grades did not express the same functional programme at the proteomic level and were characterized by different responses to the UPR induction. This study suggests that baseline cancer cell stress status could have an impact on the efficiency of cancer therapies.