Endoplasmic reticulum–resident α-glucosidase II drives non-small cell lung cancer progression via regulation of secretory glycoproteins
Shike Wang, Na Ding, Angelo Chen, Derrick Cardin, Yuting Xu, Kate Grimley, William K. Russell, Jun Xu, Jonathan M. Kurie, Guan-Yu Xiao, Xiaochao Tan
Shike Wang, Na Ding, Angelo Chen, Derrick Cardin, Yuting Xu, Kate Grimley, William K. Russell, Jun Xu, Jonathan M. Kurie, Guan-Yu Xiao, Xiaochao Tan
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Research Article Cell biology Oncology

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

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.

Authors

Shike Wang, Na Ding, Angelo Chen, Derrick Cardin, Yuting Xu, Kate Grimley, William K. Russell, Jun Xu, Jonathan M. Kurie, Guan-Yu Xiao, Xiaochao Tan

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Figure 6

GANAB regulates secretion.

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GANAB regulates secretion. (A) Representative images (left panel) and qu...
(A) Representative images (left panel) and quantification (right panel) of VSV-G trafficking assay performed in P- and GANAB-KO–344SQ cells. P values were determined using 2-tailed Student t test. (B) Representative images (left panel) and quantification (right panel) of dynamic VSV-G trafficking assay performed in shCTL- and shGANAB-A549 cells. P values were determined using 2 tailed Student’s t test. (C) Relative cell densities measured by WST-1 proliferation assays in 344SQ cells cultured in either FBS-free medium or conditioned medium collected from parental or GANAB-KO–344SQ cells. P values were determined using 2-way ANOVA. (D) Boyden chamber assays assessing migratory activity in 344SQ cells cultured in either FBS-free medium or conditioned medium collected from parental or GANAB-KO–344SQ cells. P values were determined using 1-way ANOVA. (E) Dot plot showing reduced secreted proteins in CM of both GANAB-KO–344SQ clones compared with CM of parental 344SQ cells identified by LC-MS analysis. (F) GO analysis of overlapping downregulated proteins involved in molecular function, identified in the conditioned medium of both GANAB-KO–344SQ clones compared with parental cells. Data indicate the mean ± SEM from a single experiment incorporating biological replicate samples (n ≥ 3) and are representative of at least 2 independent experiments.