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.
Keywords: IRE1α-XBP1 pathway; Metabolic reprogramming; Pyruvate dehydrogenase kinase-1 (PDK-1); Snail; Unfolded protein response (UPR).
Copyright © 2022 Elsevier Inc. All rights reserved.