Our results demonstrated that cisplatin induced PTGS2 expression through the ROS-ERK1/2-NF-κB signaling axis, and PGE2 might strengthen PTGS2 expression via the PGE2-EPs-ERK1/2 positive feedback loop, which induced multidrug resistance of NSCLC cells through up-regulation of BCL2 expression and the subsequent attenuation of cell apoptosis. The gene discussed is MAPK3; the disease is non-small cell lung carcinoma.