Cytoplasmic APE1 promotes lung cancer aggressiveness and cisplatin resistance via the COX-2/Akt/β-catenin pathway

作者：Xiaojuan Lian, Hongxu Yue, Debing Xiang, Zhimin Zhang · 发表于：Research Square · 年份：2022 · DOI：10.21203/rs.3.rs-1620610/v1 · 研究领域：Metalloenzymes and iron-sulfur proteins、Epigenetics and DNA Methylation、Cancer-related gene regulation

Abstract Background Cisplatin is commonly used in lung cancer therapy, but cisplatin resistance in lung cancer cells remains an unsolved problem. Here, we report that cytoplasmic APE1 contributes to cisplatin resistance, cell proliferation and migration in lung cancer cells. Methods Immunofluorescence, western blot analysis, lentivirus transfection and scratch assays, and transwell migration and invasion assays were carried out on the cell lines A549 and Calu-1. A total of 124 samples of lung cancer tissues were evaluated to determine the clinical effects of cytoplasmic APE1 and COX-2. Results We found that cytoplasmic APE1 expression was lower in cisplatin sensitive cells than in cisplatin-resistant cells, and the upregulation of cytoplasmic APE1 significantly reduced cisplatin sensitivity in lung cancer cells. Gain-of-function studies demonstrated that cytoplasmic APE1 promoted lung cancer cell proliferation, migration and invasion in vitro and tumor growth in vivo, which were inhibited after cisplatin treatment. In patient samples, cytoplasmic APE1 in lung cancer tissues was an independent indicator of overall survive (OS) for lung cancer patients (P < 0.001). Mechanistic studies revealed that cytoplasmic APE1 promotes lung cancer malignancy by activating the COX-2/Akt/β-catenin pathway, and that APE1-C65 site mutations can increase cytoplasmic APE1 expression and resistance to cisplatin in lung cancer cells. Conclusion We suggest that modulating cytoplasmic APE1 in lun...