EFHD2 contributes to non-small cell lung cancer cisplatin resistance by the activation of NOX4-ROS-ABCC1 axis
Chi-Chen Fan,
Sheng-Ta Tsai,
Chen-Yuan Lin,
Ling-Chu Chang,
Juan-Cheng Yang,
Guan‐Yu Chen,
Yuh-Pyng Sher,
Shao-Chun Wang,
Michael Hsiao,
Wei‐Chao Chang
Affiliations
Chi-Chen Fan
Department of Superintendent Office, Mackay Memorial Hospital, Taipei, Taiwan; Department of Medical Laboratory Science and Biotechnology, Yuanpei University, Hsinchu, Taiwan
Sheng-Ta Tsai
Genomics Research Center, Academia Sinica, Taipei, Taiwan
Chen-Yuan Lin
Department of Hematology and Oncology, China Medical University Hospital, Taichung, Taiwan; School of Pharmacy, China Medical University, Taichung, Taiwan
Ling-Chu Chang
Center for Molecular Medicine, China Medical University Hospital, China Medical University, Taichung, Taiwan; Department of Biological Science and Technology, China Medical University, Taichung, Taiwan
Juan-Cheng Yang
Department of Superintendent Office, Mackay Memorial Hospital, Taipei, Taiwan; Department of Medical Laboratory Science and Biotechnology, Yuanpei University, Hsinchu, Taiwan; Department of Post-Baccalaureate Chinese Medicine, China Medical University, Taichung, Taiwan; Chinese Medicine Research and Development Center, China Medical University Hospital, Taichung, Taiwan
Guan‐Yu Chen
Chinese Medicine Research and Development Center, China Medical University Hospital, Taichung, Taiwan
Yuh-Pyng Sher
Center for Molecular Medicine, China Medical University Hospital, China Medical University, Taichung, Taiwan; Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan; Chinese Medicine Research Center, China Medical University, Taichung, Taiwan; Research Center for Chinese Herbal Medicine, China Medical University, Taichung, Taiwan
Shao-Chun Wang
Center for Molecular Medicine, China Medical University Hospital, China Medical University, Taichung, Taiwan; Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan; Department of Cancer Biology, University of Cincinnati, Cincinnati, OH, USA; Department of Biotechnology, Asia University, Taichung, Taiwan
Michael Hsiao
Genomics Research Center, Academia Sinica, Taipei, Taiwan; Department of Biochemistry, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Corresponding author. Genomics Research Center, Academia Sinica, No. 128, Academia Road, Section 2, Nankang, Taipei, Taiwan.
Wei‐Chao Chang
Center for Molecular Medicine, China Medical University Hospital, China Medical University, Taichung, Taiwan; Corresponding author. Center for Molecular Medicine, China Medical University Hospital, No. 2, Yude Road, North District, Taichung, Taiwan.
Recurrence and metastasis remain the major cause of cancer mortality. Even for early-stage lung cancer, adjuvant 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 significantly associated with poor overall survival of NSCLC patients with chemotherapy 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 membrane expression of the ATP-binding cassette subfamily C member 1 (ABCC1) for drug efflux. Non-steroidal anti-inflammatory drug (NSAID) ibuprofen suppressed EFHD2 expression by leading to the proteasomal and lysosomal 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 individual treatment. In conclusion, we demonstrate that EFHD2 promotes chemoresistance through the NOX4-ROS-ABCC1 axis and therefore developing EFHD2-targeting strategies may offer a new avenue to improve adjuvant chemotherapy of lung cancer.
