Centre de Recherche en Cancérologie de Lyon, INSERM U1052, Centre National de la Recherche Scientifique (CNRS) 5286, Centre Léon Bérard, Université de Lyon, Université Claude Bernard Lyon 1, Lyon, France.
Institute for Regenerative Medecine and Biotherapy (IRBM), Université de Montpellier, INSERM, Montpellier, France.
Life Sci Alliance. 2022 Apr 8;5(7). doi: 10.26508/lsa.202101334. Print 2022 Jul.
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 -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.
需要葡萄糖的己糖胺生物合成途径（HBP）为糖基化反应产生 UDP-N-乙酰葡萄糖胺，促进肺腺癌（LUAD）的进展。然而，肺肿瘤细胞通常存在于营养物质匮乏的微环境中，HBP 是否参与 LUAD 对营养压力的适应尚不清楚。在这里，我们表明 HBP 和 COPII 在葡萄糖缺乏时对细胞存活起着关键作用。HBP 的上调可以抵抗低葡萄糖诱导的内质网中截断聚糖的蛋白质的产生。HBP 的这一功能，以及 COPII 的上调，挽救了一部分糖蛋白的细胞表面表达。其中包括表皮生长因子受体（EGFR），允许在无锚定生长条件下，EGFR 依赖性细胞在低葡萄糖下存活。因此，在 LUAD 患者样本中，HBP 限速酶 GFAT1 的高表达与野生型 EGFR 激活相关。值得注意的是，HBP 和 COPII 的上调将 LUAD 与肺鳞状细胞癌亚型区分开来，从而揭示了 LUAD 对其恶劣微环境的适应机制。
