Oxaliplatin and 5-fluorouracil promote epithelial-mesenchymal transition via activation of KRAS/ERK/NF-κB pathway in KRAS-mutated colon cancer cells.

Abstract

Oxaliplatin (L-OHP) and 5-fluorouracil (5-FU) are used to treat colon cancer; however, resistance contributes to poor prognosis. Epithelial-mesenchymal transition (EMT) has been induced in tumor tissues after administration of anticancer drugs and may be involved in drug resistance. We investigated the mechanism of EMT induction in colon cancer cells treated with 5-FU and L-OHP. We found that L-OHP and 5-FU at clinical steady-state concentrations induced EMT in LoVo and DLD-1 cells (KRAS G13D-mutated), but not in HT-29 and Caco-2 cells (KRAS wild type). L-OHP and 5-FU elevated vimentin, N-cadherin, Twist, Slug, and Snail and decreased E-cadherin expressions. Moreover, 5-FU- and L-OHP -induced EMT cells showed increased cell migration and decreased sensitivity to 5-FU and L-OHP. L-OHP and 5-FU treatment promoted KRAS, ERK1/2, and NF-κB activation. Combined administration with KRAS siRNA, MEK1/2 inhibitor trametinib, and NF-κB inhibitor dimethyl fumarate (DMF), suppressed L-OHP- and 5-FU-induced EMT. These results suggest that KRAS/ERK/NF-κB pathway activation is important for EMT induction by L-OHP and 5-FU treatment. Thus, MEK1/2 and NF-κB inhibitors may facilitate the resistance acquisition to L-OHP and 5-FU therapy in KRAS G13D-mutated colon cancer.