PMID- 36209899 OWN - NLM STAT- MEDLINE DCOM- 20221103 LR - 20221228 IS - 1090-2422 (Electronic) IS - 0014-4827 (Linking) VI - 421 IP - 1 DP - 2022 Dec 1 TI - IRE1alpha-XBP1 regulates PDK1-dependent induction of epithelial-mesenchymal transition in non-small cell lung cancer cells. PG - 113376 LID - S0014-4827(22)00369-X [pii] LID - 10.1016/j.yexcr.2022.113376 [doi] AB - Mounting evidence indicates that activation of unfolded protein response (UPR) and metabolic reprogramming contribute to cancer cell migration and invasion, but the molecular mechanism of pro-EMT program through a coordinated action of UPR with metabolism has not been defined. In this study, we utilized ER stress-inducing reagent, thapsigargin (TG), to induced pharmacologic ER stress in lung cancer cells. Here. We report that the branch of UPR, IRE1alpha-XBP1 pathway plays a pivotal role in reprogramming lung cancer cell metabolism. At the molecular level, the expression of pyruvate dehydrogenase kinase-1 (PDK-1) is directly induced by XBP1 as a consequence of UPR activation, thus facilitating aerobic glycolysis and lactate production. We also demonstrated that PDK1 serves as a downstream element of UPR activation in induction of Snail and EMT program. In addition, PDK1-induced Snail was dependent on the lactate production derived from metabolic reprogramming. Our findings reveal a critical role of lactate in pro-invasion events and establishes a direct connection between ER-stress and metabolic reprogramming in facilitating cancer cell progression. CI - Copyright (c) 2022 Elsevier Inc. All rights reserved. FAU - Mao, Xike AU - Mao X AD - Research Laboratory of Tumor Microenvironment, Wannan Medical College, Wuhu, 241001, China; School of Anesthesiology, Wannan Medical College, Wuhu, 241001, China. FAU - Yu, Chenxi AU - Yu C AD - Research Laboratory of Tumor Microenvironment, Wannan Medical College, Wuhu, 241001, China; School of Clinical Medicine, Wannan Medical College, Wuhu, 241001, China. FAU - Yin, Feng AU - Yin F AD - Research Laboratory of Tumor Microenvironment, Wannan Medical College, Wuhu, 241001, China; School of Clinical Medicine, Wannan Medical College, Wuhu, 241001, China. FAU - Xu, Wenjiao AU - Xu W AD - Research Laboratory of Tumor Microenvironment, Wannan Medical College, Wuhu, 241001, China; School of Clinical Medicine, Wannan Medical College, Wuhu, 241001, China. FAU - Pan, Yonghan AU - Pan Y AD - Research Laboratory of Tumor Microenvironment, Wannan Medical College, Wuhu, 241001, China; School of Clinical Medicine, Wannan Medical College, Wuhu, 241001, China. FAU - Yang, Bowen AU - Yang B AD - Research Laboratory of Tumor Microenvironment, Wannan Medical College, Wuhu, 241001, China; School of Clinical Medicine, Wannan Medical College, Wuhu, 241001, China. FAU - Huang, Tao AU - Huang T AD - Research Laboratory of Tumor Microenvironment, Wannan Medical College, Wuhu, 241001, China; School of Clinical Medicine, Wannan Medical College, Wuhu, 241001, China. FAU - Chen, Siling AU - Chen S AD - Research Laboratory of Tumor Microenvironment, Wannan Medical College, Wuhu, 241001, China; School of Medical Imageology, Wannan Medical College, Wuhu, 241001, China. FAU - Luo, Wenge AU - Luo W AD - Research Laboratory of Tumor Microenvironment, Wannan Medical College, Wuhu, 241001, China; School of Clinical Medicine, Wannan Medical College, Wuhu, 241001, China. FAU - Su, Tianyu AU - Su T AD - Research Laboratory of Tumor Microenvironment, Wannan Medical College, Wuhu, 241001, China; School of Clinical Medicine, Wannan Medical College, Wuhu, 241001, China. FAU - Wu, Zhihao AU - Wu Z AD - Research Laboratory of Tumor Microenvironment, Wannan Medical College, Wuhu, 241001, China; Anhui Province Key Laboratory of Active Biological Macro-molecules Research, Wannan Medical College, Wuhu, 241001, China; Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institution, Wannan Medical College, Wuhu, 241001, China; Provincial Engineering Laboratory for Screening and Re-evaluation of Active Compounds of Herbal Medicines in Southern Anhui, Wannan Medical College, Wuhu, 241001, China. Electronic address: zwu2ster@wnmc.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20221006 PL - United States TA - Exp Cell Res JT - Experimental cell research JID - 0373226 RN - EC 3.1.- (Endoribonucleases) RN - 0 (Lactates) RN - EC 2.7.11.1 (Protein Serine-Threonine Kinases) RN - 0 (Pyruvate Dehydrogenase Acetyl-Transferring Kinase) RN - 67526-95-8 (Thapsigargin) RN - 0 (X-Box Binding Protein 1) RN - 0 (XBP1 protein, human) RN - 0 (PDK1 protein, human) SB - IM MH - Humans MH - *Carcinoma, Non-Small-Cell Lung/genetics/metabolism MH - Endoplasmic Reticulum Stress MH - *Endoribonucleases/genetics/metabolism MH - *Epithelial-Mesenchymal Transition/genetics MH - Lactates MH - Lung Neoplasms/genetics MH - Protein Serine-Threonine Kinases/genetics MH - *Pyruvate Dehydrogenase Acetyl-Transferring Kinase/genetics/metabolism MH - Thapsigargin MH - Unfolded Protein Response MH - *X-Box Binding Protein 1/genetics/metabolism OTO - NOTNLM OT - IRE1alpha-XBP1 pathway OT - Metabolic reprogramming OT - Pyruvate dehydrogenase kinase-1 (PDK-1) OT - Snail OT - Unfolded protein response (UPR) COIS- Declaration of competing interest The authors declare that they have no competing interests. EDAT- 2022/10/10 06:00 MHDA- 2022/10/26 06:00 CRDT- 2022/10/09 19:23 PHST- 2022/08/21 00:00 [received] PHST- 2022/10/02 00:00 [revised] PHST- 2022/10/03 00:00 [accepted] PHST- 2022/10/10 06:00 [pubmed] PHST- 2022/10/26 06:00 [medline] PHST- 2022/10/09 19:23 [entrez] AID - S0014-4827(22)00369-X [pii] AID - 10.1016/j.yexcr.2022.113376 [doi] PST - ppublish SO - Exp Cell Res. 2022 Dec 1;421(1):113376. doi: 10.1016/j.yexcr.2022.113376. Epub 2022 Oct 6.