Despite the recent advances achieved in the treatment of colon cancer, tumour resistance is a frequent cause of chemotherapy failure. Our work was aimed to determine the molecular mechanisms involved in the resistance to camptothecin (SN38), an anticancer agent widely used in colorectal cancer treatment. To this end, we establish an SN38-resistant cellular model from the colon adenocarcinoma cell line HCT-116. Among cellular clones obtained, one displaying mild resistance (6 fold, and called SN6) was very interesting because any camptothecin resistance mechanisms already reported was observed. We then addressed the question of which signalling pathway is involved in this drug resistance. Using specific inhibitors for each MAPK (Erk, Jnk and p38) or for AKT, we observed that the p38 MAPK is activated in the SN6 cells compared to HCT-116 (Gongora et al, Cancer Biol Ther. 2008 Jun; 7(6):822-32), and this activation is responsible for the SN38 resistance. Knowing that the p38 MAPK family is composed of 4 isoforms, we have constructed cell lines overexpressing or inhibiting each p38 isoforms. These tools permited to analyse the role of each p38 isoforms in cell proliferation, cell motility, cell cycle, apoptosis and SN38 resistance, and we identified the isoforms \#945; and \#946; as the one responsible for drug resistance and for other cellular effects. Interestingly, one of the isoform that we have identified in vitro, display an overexpression in patients non responder to a combination of Irinotecan and 5-FU (FOLFIRI). These data indicate that p38 may be a new target in overcoming drug resistance in colon cancer patients.
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|Published - 2009