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NDRG1 disruption alleviates cisplatin/sodium glycididazole-induced DNA damage response and apoptosis in ERCC1-defective lung cancer cells

He, Lang, Liu, Kang, Wang, Xiaoshan, Chen, Hong, Zhou, Jin, Wu, Xun, Liu, Tao, Yang, Yongxue, Yang, Xuemei, Cui, Dandan, Song, Guiqin, Wang, un, Lei, Jianguo
The international journal of biochemistry & cell biology 2018 v.100 pp. 54-60
DNA damage, DNA repair, Western blotting, apoptosis, cisplatin, drug resistance, drug therapy, flow cytometry, genes, humans, lung neoplasms, neoplasm cells, sequence analysis, stress response
Resistance to platinum-based chemotherapy becomes a major obstacle in lung cancer treatment. Compensatory activation of nucleotide excision repair (NER) pathway is the major mechanism accounting for cisplatin-resistance. We aimed at identifying additional regulators in NER-mediated chemoresistance in a hypoxic setting induced by sodium glycididazole (CMNa)-sensitized cisplatin chemotherapy of non-small cell lung cancer (NSCLC).We performed an RNA-sequencing (RNA-Seq) analysis to identify the genes whose expression had been differentially regulated in NER-deficient cells that had been treated by cisplatin/CMNa. DNA damage, apoptosis, and correlational analysis between the differentially expressed gene and drug sensitivity were determined by Western blots, flow cytometry and Oncomine expression analysis.The stress response gene, NDRG1 (N-Myc downstream-regulated gene 1), was among the differentially expressed genes in NER-deficient cells upon treatment of cisplatin/CMNa. Downregulation of NDRG1 by ERCC1 (excision repair cross-complementing 1) could be a prevalent mechanism for drug resistance. Furthermore, lower NDRG1 level is observed in human lung cancer cells showing chemotherapeutic drug resistance compared with the drug-sensitive cells.NDRG1 is an important modulator linking DNA damage response and hypoxia-related cellular stress response during the development of drug resistance to cisplatin/CMNa in lung cancer. Targeting both NDRG1 and ERCC1 may be a viable strategy for overcoming drug resistance in cancer therapy, and has significant clinical implications.