2. Academic Validation
  3. Endoplasmic reticulum-resident α-glucosidase II drives non-small cell lung cancer progression via regulation of secretory glycoproteins

Endoplasmic reticulum-resident α-glucosidase II drives non-small cell lung cancer progression via regulation of secretory glycoproteins

  • JCI Insight. 2026 Jun 8;11(11):e203262. doi: 10.1172/jci.insight.203262.
Shike Wang 1,  Na Ding 2,  Angelo Chen 3,  Derrick Cardin 4,  Yuting Xu 4,  Kate Grimley 5,  William K Russell 6,  Jun Xu 7,  Jonathan M Kurie 2,  Guan-Yu Xiao 8,  Xiaochao Tan 1
Affiliations

Affiliations

  • 1 Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Texas, USA.
  • 2 Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
  • 3 Department of Biosciences, Rice University, Houston, Texas, USA.
  • 4 Department of Medicine, Section of Hematology Oncology, Tulane University School of Medicine, Louisiana Cancer Research Center, New Orleans, Louisiana, USA.
  • 5 Hillsdale College, Hillsdale, Michigan, USA.
  • 6 Department of Biochemistry & Molecular Biology, The University of Texas Medical Branch at Galveston, Houston, Texas, USA.
  • 7 Molecular and Cellular Biology Department, The Advanced Cell Engineering and 3D Models Core, Baylor College of Medicine, Houston, Texas, USA.
  • 8 Department of Toxicology and Cancer Biology, The University of Kentucky, Lexington, Kentucky, USA.
PMID: 42258751 DOI: 10.1172/jci.insight.203262
Abstract

Non-small cell lung Cancer (NSCLC) remains a leading cause of cancer-related mortality worldwide, yet its molecular drivers are not fully defined. Emerging evidence highlights the importance of tumor-stroma interactions mediated by secreted glycoproteins. However, the mechanisms by which Cancer cells regulate the secretion of these protumorigenic proteins remain largely unknown. Endoplasmic reticulum-resident (ER-resident) N-glycan-processing Enzymes regulate proper protein folding, a prerequisite for glycoproteins to exit the ER and undergo secretion. By evaluating their prognostic significance in lung tumors and conducting functional screening in lung Cancer cells, we identify α-glucosidase II (α-Glc II) as a key regulator of NSCLC progression. α-Glc II promotes tumor growth and dissemination in a glucosidase activity-dependent manner in orthotopic mouse lung tumor model. Genetic disruption of α-Glc II induced ER stress and reduced cell proliferation and motility. Mechanistically, α-Glc II-mediated N-glycan modification regulated the ER-to-Golgi trafficking and secretion of specific oncogenic glycoproteins, including lysyl hydroxylase 2 (LH2), Tissue Inhibitor of Metalloproteinase 1 (TIMP1), and TGF-β, which are known to be associated with extracellular matrix remodeling. These findings uncover a role for ER glycosylation machinery in shaping the NSCLC secretome and highlight α-Glc II as a potential therapeutic target.

Keywords

Cancer; Cell biology; Lung cancer; Oncology; Protein traffic.

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