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

Abstract

The glucose-requiring hexosamine biosynthetic pathway (HBP), which produces UDP-N-acetylglucosamine for glycosylation reactions, promotes lung adenocarcinoma (LUAD) progression. However, lung tumor cells often reside in low-nutrient microenvironments, and whether the HBP is involved in the adaptation of LUAD to nutrient stress is unknown. Here, we show that the HBP and the coat complex II (COPII) play a key role in cell survival during glucose shortage. HBP up-regulation withstood low glucose-induced production of proteins bearing truncated N-glycans, in the endoplasmic reticulum. This function for the HBP, alongside COPII up-regulation, rescued cell surface expression of a subset of glycoproteins. Those included the epidermal growth factor receptor (EGFR), allowing an EGFR-dependent cell survival under low glucose in anchorage-independent growth. Accordingly, high expression of the HBP rate-limiting enzyme GFAT1 was associated with wild-type EGFR activation in LUAD patient samples. Notably, HBP and COPII up-regulation distinguished LUAD from the lung squamous-cell carcinoma subtype, thus uncovering adaptive mechanisms of LUAD to their harsh microenvironment.

O-GlcNAc Dynamics: The Sweet Side of Protein Trafficking Regulation in Mammalian Cells

“…High glucose levels decrease Sec31A O-GlcNAcylation compared to a lower glucose concentration, while the steady-state level of Sec31A remains unchanged [80]. Interestingly, COPII subunits are also regulated at a transcriptional level in response to nutrient availability fluctuations [86,87]. In particular, glucose shortage (0.1/1 mM) increases the mRNA levels of several COPII-coat Sec proteins in human bronchial epithelial cells.…”

“…In particular, glucose shortage (0.1/1 mM) increases the mRNA levels of several COPII-coat Sec proteins in human bronchial epithelial cells. In this case, COPII upregulation is needed to counterbalance the loss of EGFR at the cell surface in this scarce nutritional condition [87]. It would be interesting to determine whether changes in O-GlcNAc levels onto COPII-Sec components are at the forefront of the molecular mechanisms to rapidly adjust COPII anterograde transport in response to nutrient excess or shortage, before the induction of a more comprehensive response through transcriptional mechanisms.…”

Energy metabolism as the hub of advanced non-small cell lung cancer management: a comprehensive view in the framework of predictive, preventive, and personalized medicine

“…In the light of the upregulation of glucose-requiring hexosamine biosynthetic pathway (HBP) and the coat complex II (COPII), LUAD and LUSC subtypes can be distinguished based on their adaptive mechanisms of the TME even in glucose-deprived conditions. Herein, high expression of GFAT1 (HBP rate-limiting enzyme) is associated with wild-type EGRF activation [ 67 ]. The flavone cirsilineol can inhibit the proliferation of NCIH-520 cells through the induction of ROS-mediated apoptosis [ 68 ].…”

Adaptations of membrane trafficking in cancer and tumorigenesis

“…Aberrant EGFR trafficking and glycosylation is linked to resistance to therapeutic tyrosine kinase inhibitors, which are critical treatment options for breast and non-small lung cancer ( Sambrooks et al, 2018 ; Scharaw et al, 2016 ). EGFR is highly N-glycosylated in the ER and Golgi, and its transport to the plasma membrane is sensitive to aberrant glycosylation and expression of the COPII inner coat complex proteins SEC23B, SEC24B and SEC24D ( Dragic et al, 2022 ; Scharaw et al, 2016 ).…”