PMID- 30922965 OWN - NLM STAT- MEDLINE DCOM- 20190820 LR - 20211204 IS - 2352-3964 (Electronic) IS - 2352-3964 (Linking) VI - 42 DP - 2019 Apr TI - PDIA6 modulates apoptosis and autophagy of non-small cell lung cancer cells via the MAP4K1/JNK signaling pathway. PG - 311-325 LID - S2352-3964(19)30190-2 [pii] LID - 10.1016/j.ebiom.2019.03.045 [doi] AB - BACKGROUND: 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. METHODS: 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. FINDINGS: 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. INTERPRETATION: 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. FUND: National Natural Science Foundation of China and Institutions of higher learning of innovation team from Liaoning province. CI - Copyright (c) 2019 The Authors. Published by Elsevier B.V. All rights reserved. FAU - Bai, Yuxin AU - Bai Y AD - Key Laboratory of Proteomics, Dalian Medical University, Dalian 116044, China. FAU - Liu, Xuefeng AU - Liu X AD - Institute of Cancer Stem Cell, Dalian Medical University, Dalian 116044, China. FAU - Qi, Xiaoyu AU - Qi X AD - Key Laboratory of Proteomics, Dalian Medical University, Dalian 116044, China. FAU - Liu, Xuan AU - Liu X AD - Key Laboratory of Proteomics, Dalian Medical University, Dalian 116044, China. FAU - Peng, Fang AU - Peng F AD - Key Laboratory of Proteomics, Dalian Medical University, Dalian 116044, China. FAU - Li, Huimin AU - Li H AD - Key Laboratory of Proteomics, Dalian Medical University, Dalian 116044, China. FAU - Fu, Hailu AU - Fu H AD - Key Laboratory of Proteomics, Dalian Medical University, Dalian 116044, China. FAU - Pei, Shimei AU - Pei S AD - Key Laboratory of Proteomics, Dalian Medical University, Dalian 116044, China. FAU - Chen, Liying AU - Chen L AD - Key Laboratory of Proteomics, Dalian Medical University, Dalian 116044, China. FAU - Chi, Xinming AU - Chi X AD - Key Laboratory of Proteomics, Dalian Medical University, Dalian 116044, China. FAU - Zhang, Liyuan AU - Zhang L AD - Key Laboratory of Proteomics, Dalian Medical University, Dalian 116044, China. FAU - Zhu, Xinbing AU - Zhu X AD - Institute of Cancer Stem Cell, Dalian Medical University, Dalian 116044, China. FAU - Song, Yang AU - Song Y AD - Key Laboratory of Proteomics, Dalian Medical University, Dalian 116044, China. FAU - Wang, Yang AU - Wang Y AD - Institute of Cancer Stem Cell, Dalian Medical University, Dalian 116044, China. FAU - Meng, Songshu AU - Meng S AD - Institute of Cancer Stem Cell, Dalian Medical University, Dalian 116044, China. FAU - Jiang, Tao AU - Jiang T AD - Department of Andrology, The First Hospital Affiliated of Dalian Medical University, Dalian 116011, China. Electronic address: jiangt69@163.com. FAU - Shao, Shujuan AU - Shao S AD - Key Laboratory of Proteomics, Dalian Medical University, Dalian 116044, China. Electronic address: shaoshujuan2006@126.com. LA - eng PT - Journal Article DEP - 20190325 PL - Netherlands TA - EBioMedicine JT - EBioMedicine JID - 101647039 RN - 0 (Antineoplastic Agents) RN - 0 (Biomarkers, Tumor) RN - EC 2.7.1.11 (hematopoietic progenitor kinase 1) RN - EC 2.7.11.1 (Protein Serine-Threonine Kinases) RN - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases) RN - EC 3.4.22.- (Caspases) RN - EC 5.3.4.1 (PDIA6 protein, human) RN - EC 5.3.4.1 (Protein Disulfide-Isomerases) CIN - EBioMedicine. 2019 Apr;42:20-21. PMID: 30956170 MH - Adult MH - Aged MH - Animals MH - Antineoplastic Agents/pharmacology MH - *Apoptosis/drug effects/genetics MH - *Autophagy/drug effects/genetics MH - Biomarkers, Tumor MH - Carcinoma, Non-Small-Cell Lung/genetics/*metabolism/mortality/pathology MH - Caspases/metabolism MH - Cell Line, Tumor MH - Cell Proliferation MH - Female MH - Humans MH - Immunohistochemistry MH - JNK Mitogen-Activated Protein Kinases/metabolism MH - Lung Neoplasms/genetics/*metabolism/mortality/pathology MH - *MAP Kinase Signaling System MH - Male MH - Mice MH - Middle Aged MH - Models, Biological MH - Neoplasm Grading MH - Neoplasm Staging MH - Prognosis MH - Protein Disulfide-Isomerases/genetics/*metabolism MH - Protein Serine-Threonine Kinases/metabolism PMC - PMC6491656 OTO - NOTNLM OT - Apoptosis OT - Autophagy OT - MAP4K1 OT - NSCLC OT - PDIA6 EDAT- 2019/03/30 06:00 MHDA- 2019/08/21 06:00 PMCR- 2019/03/25 CRDT- 2019/03/30 06:00 PHST- 2019/02/18 00:00 [received] PHST- 2019/03/15 00:00 [revised] PHST- 2019/03/15 00:00 [accepted] PHST- 2019/03/30 06:00 [pubmed] PHST- 2019/08/21 06:00 [medline] PHST- 2019/03/30 06:00 [entrez] PHST- 2019/03/25 00:00 [pmc-release] AID - S2352-3964(19)30190-2 [pii] AID - 10.1016/j.ebiom.2019.03.045 [doi] PST - ppublish SO - EBioMedicine. 2019 Apr;42:311-325. doi: 10.1016/j.ebiom.2019.03.045. Epub 2019 Mar 25.