Regulation of ABCG2 by nuclear factor kappa B affects the sensitivity of human lung adenocarcinoma A549 cells to arsenic trioxide.

Arsenic trioxide (As2O3) is successfully used as an anticancer agent against acute promyelocytic leukemia and some solid tumors. However, the application of As2O3 is largely limited by its drug resistance in the treatment of non-small cell lung carcinoma (NSCLC). Therefore, it is an urgent task to enhance the sensitivity of lung cancer cells to As2O3. In this study, using human lung adenocarcinoma A549 cells as a cell culture model, we demonstrated that an adenosine triphosphate binding cassette (ABC) transporter, ABCG2, was significantly increased by As2O3 treatment, while other ABC transporters, ABCB1 and ABCC1 showed no remarkable change in the response to As2O3. After inhibition of ABCG2 by its specific inhibitor, the drug sensitivity of As2O3 to A549 cells was significantly enhanced, manifested by decreased cell viability and colony formation as well as the increased ROS production and cell apoptosis. To further understand the molecular mechanism underlying the elevation of ABCG2 expression in As2O3-treated cells, we detected the activation state of nuclear factor kappa B (NF-κB) pathway and its relationship with ABCG2 expression. Our results revealed that the increased expression of ABCG2 was regulated by NF-κB, and thus affecting the cell death of As2O3-treated A549 cells. These findings indicate that inhibition of NF-κB/ABCG2 pathway by specific inhibitors may be a new strategy for the improvement of As2O3 sensitivity in NSCLC treatment.