The hexosamine pathway and coat complex II promote malignant adaptation to nutrient scarcity

Area of Science:

• Cell Biology
• Cancer Biology
• Biochemistry

Background:

• Lung adenocarcinoma (LUAD) progression is linked to the hexosamine biosynthetic pathway (HBP).
• LUAD cells often face nutrient-limited microenvironments, but their adaptive mechanisms to glucose stress are unclear.
• The role of HBP in LUAD adaptation to nutrient stress remains unknown.

Purpose of the Study:

• To investigate the role of the HBP in LUAD cell survival under glucose-limiting conditions.
• To explore the involvement of coat complex II (COPII) in LUAD adaptation to nutrient stress.
• To identify adaptive mechanisms enabling LUAD to thrive in harsh microenvironments.

Main Methods:

• Analysis of HBP and COPII function during glucose deprivation in LUAD cells.
• Assessment of N-glycan truncation and glycoprotein expression under low glucose.
• Evaluation of epidermal growth factor receptor (EGFR) surface expression and signaling.
• Correlation of GFAT1 and EGFR expression with LUAD patient data.
• Comparative analysis of HBP and COPII upregulation in LUAD versus lung squamous-cell carcinoma.

Main Results:

• HBP upregulation counteracted low glucose-induced N-glycan truncation in the endoplasmic reticulum.
• HBP and COPII upregulation restored cell surface glycoprotein expression, including EGFR.
• EGFR-dependent cell survival was observed under low glucose conditions during anchorage-independent growth.
• High GFAT1 expression correlated with wild-type EGFR activation in LUAD patient samples.
• Upregulation of HBP and COPII differentiated LUAD from lung squamous-cell carcinoma.

Conclusions:

• The HBP and COPII are critical for LUAD cell survival under glucose shortage.
• These pathways facilitate adaptive mechanisms allowing LUAD to overcome nutrient stress.
• Targeting HBP and COPII may offer therapeutic strategies for LUAD, particularly in nutrient-poor tumor microenvironments.