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

  • Exp Cell Res. 2022 Oct 6;113376. doi: 10.1016/j.yexcr.2022.113376.
Xike Mao  1 ,  Chenxi Yu  2 ,  Feng Yin  2 ,  Wenjiao Xu  2 ,  Yonghan Pan  2 ,  Bowen Yang  2 ,  Tao Huang  2 ,  Siling Chen  3 ,  Wenge Luo  2 ,  Tianyu Su  2 ,  Zhihao Wu  4
Affiliations
  • 1. Research Laboratory of Tumor Microenvironment, Wannan Medical College, Wuhu, 241001, China; School of Anesthesiology, Wannan Medical College, Wuhu, 241001, China.
  • 2. Research Laboratory of Tumor Microenvironment, Wannan Medical College, Wuhu, 241001, China; School of Clinical Medicine, Wannan Medical College, Wuhu, 241001, China.
  • 3. Research Laboratory of Tumor Microenvironment, Wannan Medical College, Wuhu, 241001, China; School of Medical Imageology, Wannan Medical College, Wuhu, 241001, China.
  • 4. 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: [email protected].
PMID: 36209899 DOI: 10.1016/j.yexcr.2022.113376
Abstract

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).
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