EFHD2 contributes to non-small cell lung cancer cisplatin resistance by the activation of NOX4-ROS-ABCC1 axis
| Autor: | Juan-Cheng Yang, Michael Hsiao, Yuh Pyng Sher, Wei Chao Chang, Guan Yu Chen, Sheng-Ta Tsai, Chen Yuan Lin, Shao Chun Wang, Ling-Chu Chang, Chi-Chen Fan |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Lung Neoplasms medicine.medical_treatment Clinical Biochemistry ABCC1 Ibuprofen Biochemistry Metastasis NOX4 03 medical and health sciences Mice 0302 clinical medicine Recurrence Carcinoma Non-Small-Cell Lung Cell Line Tumor medicine EFHD2 Animals Humans Lung cancer lcsh:QH301-705.5 Cisplatin lcsh:R5-920 Gene knockdown Chemotherapy NADPH oxidase biology business.industry Organic Chemistry Calcium-Binding Proteins medicine.disease Adjuvant chemotherapy 030104 developmental biology lcsh:Biology (General) Drug Resistance Neoplasm NADPH Oxidase 4 biology.protein Cancer research Cyclooxygenase Multidrug Resistance-Associated Proteins lcsh:Medicine (General) business Reactive Oxygen Species 030217 neurology & neurosurgery medicine.drug Research Paper Signal Transduction |
| Zdroj: | Redox Biology Redox Biology, Vol 34, Iss, Pp 101571-(2020) |
| ISSN: | 2213-2317 |
| Popis: | 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. Highlights • EFHD2 increases resistance of lung cancer to cisplatin. • EFHD2 enhances the NOX4-ROS-ABCC1signalingfor cisplatin efflux. • Ibuprofen suppresses EFHD2 through both proteasomal and lysosomal degradationmechanisms |
| Databáze: | OpenAIRE |
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