NFκB-Associated Pathways in Progression of Chemoresistance to 5-Fluorouracil in an In Vitro Model of Colonic Carcinoma.

ABSTRACT

BACKGROUND: Drug resistance to 5-fluorouracil (5-FU) is a major obstacle in colonic cancer treatment. Activation of nuclear factor-kappa B (NFκB), mitogen-activated protein kinase kinase kinase 8 (MAP3K8) and protein kinase B (AKT) is thought to protect cancer cells against therapy-induced cytotoxicity. MATERIALS AND METHODS: Using cytotoxicity assays and immunoblotting, the impact of inhibitory strategies addressing NFκB, AKT and MAP3K8 in chemoresistance was evaluated in a colonic cancer model in vitro. This model consisted of the cell lines SW480 and SW620, and three subclones with increasing degrees of chemoresistance in order to mimic the development of secondary resistance. RESULTS: NFκB protein p65 was selectively activated in all resistant cell lines. Consequently, several inhibitors of NFκB, MAP3K8 and AKT effectively circumvented this chemoresistance. As a cellular reaction, NFκB inhibition may trigger a feedback loop resulting in activation of extracellular signal-regulated kinase. The results suggest that chemoresistance to 5-FU in this colonic carcinoma model (cell lines SW480 and SW620) is strongly dependent on NFκB activation. The efficacy of MAP3K8 inhibition in our model potentially uncovers a new mechanism to circumvent 5-FU resistance.