PDIA6 modulates apoptosis and autophagy of non-small cell lung cancer cells via the MAP4K1/JNK signaling pathway

• Published in: EBioMedicine Vol. 42; pp. 311 - 325
• Main Authors: Bai, Yuxin, Liu, Xuefeng, Qi, Xiaoyu, Liu, Xuan, Peng, Fang, Li, Huimin, Fu, Hailu, Pei, Shimei, Chen, Liying, Chi, Xinming, Zhang, Liyuan, Zhu, Xinbing, Song, Yang, Wang, Yang, Meng, Songshu, Jiang, Tao, Shao, Shujuan
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.04.2019; Elsevier
• Subjects: Adult; Aged; Animals; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Apoptosis - genetics; Autophagy; Autophagy - drug effects; Autophagy - genetics; Biomarkers, Tumor; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - mortality; Carcinoma, Non-Small-Cell Lung - pathology; Caspases - metabolism; Cell Line, Tumor; Cell Proliferation; Female; Humans; Immunohistochemistry; JNK Mitogen-Activated Protein Kinases - metabolism; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - mortality; Lung Neoplasms - pathology; Male; MAP Kinase Signaling System; MAP4K1; Mice; Middle Aged; Models, Biological; Neoplasm Grading; Neoplasm Staging; NSCLC; PDIA6; Prognosis; Protein Disulfide-Isomerases - genetics; Protein Disulfide-Isomerases - metabolism; Protein-Serine-Threonine Kinases - metabolism; Research paper; MAP4K1; NSCLC; PDIA6; Autophagy; Apoptosis
• ISSN: 2352-3964; 2352-3964
• DOI: 10.1016/j.ebiom.2019.03.045

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer with a poor prognosis. We previously found that protein disulfide isomerase family 6 (PDIA6) is upregulated in lung squamous cell carcinoma (LSCC). This study aimed to elucidate the clinical relevance, biological functions, and molecular mechanisms of PDIA6 in NSCLC. The expression of PDIA6 in NSCLC was assessed using the TCGA database, western blotting, and immunohistochemistry. Correlations of PDIA6 expression with clinicopathological and survival features were evaluated. The functions of PDIA6 in regulating NSCLC cell growth, apoptosis, and autophagy were investigated using gain-and loss-of-function strategies in vitro or in vivo. The underlying molecular mechanisms of PDIA6 function were examined by human phospho-kinase array and co-immunoprecipitation. PDIA6 expression was upregulated in NSCLC compared with adjacent normal tissues, and the higher PDIA6 expression was correlated with poor prognosis. PDIA6 knockdown decreased NSCLC cell proliferation and increased cisplatin-induced intrinsic apoptosis, while PDIA6 overexpression had the opposite effects. In addition, PDIA6 regulated cisplatin-induced autophagy, and this contributed to PDIA6-mediated apoptosis in NSCLC cells. Mechanistically, PDIA6 reduced the phosphorylation levels of JNK and c-Jun. Moreover, PDIA6 interacted with MAP4K1 and inhibited its phosphorylation, ultimately inhibiting the JNK/c-Jun signaling pathway. PDIA6 is overexpressed in NSCLC and inhibits cisplatin-induced NSCLC cell apoptosis and autophagy via the MAP4K1/JNK/c-Jun signaling pathway, suggesting that PDIA6 may serve as a biomarker and therapeutic target for NSCLC patients. National Natural Science Foundation of China and Institutions of higher learning of innovation team from Liaoning province.