CLDN1 Increases Drug Resistance of Non-Small Cell Lung Cancer by Activating Autophagy via Up-Regulation of ULK1 Phosphorylation
Zhenhuan Zhao, Jing Li, Yan Jiang, Wen Xu, Xin Li, Weili Jing
Department of Pharmacy, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China (mainland)
Med Sci Monit 2017; 23:2906-2916
The aim of this study was to investigate the expression of CLDN1 in non-small cell lung cancer (NSCLC) and its mechanism of action in cisplatin resistance.
MATERIAL AND METHODS: A total of 55 patients with NSCLC admitted to our hospital between October 2013 and October 2015 were included. NSCLC tissues and tumor-adjacent tissues (≥5 cm from tumor edge) were collected. Among the 55 patients, 37 had adenocarcinoma and 18 had squamous cell carcinoma. Quantitative real-time polymerase chain reaction was used to determine mRNA expression, and protein expression was examined using Western blotting. CCK-8 assay was used to determine cell proliferation and Transwell assay was used to detect migration and invasion of the cells. Confocal microscopy was used to observe autophagosomes.
RESULTS: Increased CLDN1 expression promoted the development and metastasis of NSCLC. CLDN1 expression in A549/CDDP cells was up-regulated at both transcriptional and translational levels. Reduced CLDN1 expression decreased the drug resistance, proliferation, migration, and invasion abilities of A549/CDDP cells. Decreased CLDN1 expression promoted the apoptosis of A549/CDDP cells. CLDN1 enhanced CDDP drug resistance of A549 cells by activating autophagy. CLDN1 promoted the autophagy of A549 cells by up-regulating the phosphorylation level of ULK1.
CONCLUSIONS: The present study demonstrates that expression of CLDN1 in NSCLC is up-regulated and it is correlated with clinicopathological features. CLDN1 activates autophagy through up-regulation of ULK1 phosphorylation and promotes drug resistance of NSCLC cells to CDDP.
Keywords: Autophagy, Carcinoma, Non-Small-Cell Lung, Claudin-1