EFHD2 contributes to non-small cell lung cancer cisplatin resistance by the activation of NOX4-ROS-ABCC1 axis

Recurrence and metastasis remain the major cause of cancer mortality. Even for early-stage lung cancer, ad-juvant chemotherapy yields merely slight increase to patient survival. EF-hand domain-containing protein D2 (EFHD2) has recently been implicated in recurrence of patients with stage I lung adenocarcinoma. In this study, we investigated the correlation between EFHD2 and chemoresistance in non-small cell lung cancer (NSCLC). High expression of EFHD2 was signi ficantly associated with poor overall survival of NSCLC patients with che-motherapy in in silica analysis. Ectopic EFHD2 overexpression increased cisplatin resistance, whereas EFHD2 knockdown improved chemoresponse. Mechanistically, EFHD2 induced the production of NADPH oxidase 4 (NOX4) and in turn the increase of intracellular reactive oxygen species (ROS), consequently activating mem-brane expression of the ATP-binding cassette subfamily C member 1 (ABCC1) for drug e fflux. Non-steroidal anti-in flammatory drug (NSAID) ibuprofen suppressed EFHD2 expression by leading to the proteasomal and lyso-somal degradation of EFHD2 through a cyclooxygenase (COX)-independent mechanism. Combining ibuprofen with cisplatin enhanced antitumor responsiveness in a murine xenograft model in comparison with the in-dividual treatment. In conclusion, we demonstrate that EFHD2 promotes chemoresistance through the NOX4-ROS-ABCC1 axis and therefore developing EFHD2-targeting strategies may o ffer a new avenue to improve ad-juvant chemotherapy of lung cancer.