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

Abstract

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.

• Authors: 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
• Journal: Redox biology (Redox Biol) Vol. 34 Pg. 101571 (07 2020) ISSN: 2213-2317 [Electronic] Netherlands
• PMID: 32446175 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.

Chemical References

• Calcium-Binding Proteins
• EFHD2 protein, human
• Multidrug Resistance-Associated Proteins
• Reactive Oxygen Species
• NADPH Oxidase 4
• NOX4 protein, human
• Cisplatin
• multidrug resistance-associated protein 1

Topics

• Animals
• Calcium-Binding Proteins
• Carcinoma, Non-Small-Cell Lung (drug therapy, genetics)
• Cell Line, Tumor
• Cisplatin (pharmacology, therapeutic use)
• Drug Resistance, Neoplasm (genetics)
• Humans
• Lung Neoplasms (drug therapy, genetics)
• Mice
• Multidrug Resistance-Associated Proteins
• NADPH Oxidase 4 (genetics, metabolism)
• Reactive Oxygen Species (metabolism)
• Signal Transduction