IRE1α-XBP1 regulates PDK1-dependent induction of epithelial-mesenchymal transition in non-small cell lung cancer cells

• Published in: Experimental cell research Vol. 421; no. 1; p. 113376
• Main Authors: Mao, Xike, Yu, Chenxi, Yin, Feng, Xu, Wenjiao, Pan, Yonghan, Yang, Bowen, Huang, Tao, Chen, Siling, Luo, Wenge, Su, Tianyu, Wu, Zhihao
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.12.2022
• Subjects: Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - metabolism; Endoplasmic Reticulum Stress; Endoribonucleases - genetics; Endoribonucleases - metabolism; Epithelial-Mesenchymal Transition - genetics; Humans; IRE1α-XBP1 pathway; Lactates; Lung Neoplasms - genetics; Metabolic reprogramming; Protein Serine-Threonine Kinases - genetics; Pyruvate Dehydrogenase Acetyl-Transferring Kinase - genetics; Pyruvate Dehydrogenase Acetyl-Transferring Kinase - metabolism; Pyruvate dehydrogenase kinase-1 (PDK-1); Snail; Thapsigargin; Unfolded Protein Response; Unfolded protein response (UPR); X-Box Binding Protein 1 - genetics; X-Box Binding Protein 1 - metabolism; Pyruvate dehydrogenase kinase-1 (PDK-1); IRE1α-XBP1 pathway; Metabolic reprogramming; Snail; Unfolded protein response (UPR)
• ISSN: 0014-4827; 1090-2422
• DOI: 10.1016/j.yexcr.2022.113376

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, IRE1α-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. •The branch of unfolded protein response (UPR), IRE1α-XBP1 pathway drives lung cancer cell metabolism reprogramming.•PDK-1 is a key downstream target of IRE1α-XBP1 pathway mediating epithelial-mesenchymal transition (EMT).•PDK1-induced Snail and EMT program was dependent on the lactate production derived from metabolic reprogramming.