ERK1-mediated GLYCTK2 phosphorylation promotes fructolysis to sustain glioblastoma survival under glucose deprivation.

in Cell death discovery by Yingping Li, Fenna Zhang, Fumin Hu, Rui Tong, Yueqi Wen, Guokai Fu, Xueli Bian

TLDR

  • The study identifies GLYCTK2 as a glucose-sensing metabolic checkpoint that maintains GBM cell survival under glucose deprivation, and proposes targeting GLYCTK2 as a potential therapeutic strategy.

Abstract

Metabolic plasticity sustains glioblastoma (GBM) survival under nutrient stress, yet how fructolytic adaptation compensates for glucose deprivation remains unclear. Here, we identify glycerate kinase 2 (GLYCTK2) as a glucose-sensing metabolic checkpoint that maintains GBM cell viability through ERK1-mediated phosphorylation. Mechanistically, glucose deprivation-activated ERK1 phosphorylates GLYCTK2 at serine 220 directly, which prevents STUB1 (ubiquitin E3 ligase) binding, thereby abrogating the ubiquitination and degradation of GLYCTK2. Importantly, Functional studies demonstrated that fructose supplementation rescues glucose deprivation-induced death in wild-type GBM cells, but fails to protect GLYCTK2-depleted cells, establishing GLYCTK2 as the gatekeeper of fructolytic salvage pathways. These findings demonstrate an important mechanism by which GBM cells rewire glucose metabolism to fructose metabolism via phosphorylating and stabilizing GLYCTK2 to maintain GBM cell survival under glucose deprivation condition, underscoring the potential to target GLYCTK2 for the treatment of patients with GBM.

Overview

  • The study investigates how glioblastoma (GBM) cells sustain their survival under nutrient stress, specifically glucose deprivation.
  • The researchers identify glycerate kinase 2 (GLYCTK2) as a glucose-sensing metabolic checkpoint that maintains GBM cell viability under glucose deprivation.
  • The study aims to understand how GBM cells adapt to glucose deprivation and identify potential targets for therapy.

Comparative Analysis & Findings

  • The study finds that glucose deprivation activates ERK1, which phosphorylates GLYCTK2 at serine 220, preventing STUB1 binding and subsequent ubiquitination and degradation.
  • GLYCTK2 depletion abolishes fructose supplementation's protective effect against glucose deprivation-induced death in GBM cells.
  • Functional studies demonstrate that fructose supplementation rescues glucose deprivation-induced death in wild-type GBM cells.

Implications and Future Directions

  • The study suggests that targeting GLYCTK2 could be a potential strategy for treating patients with GBM.
  • Future studies could explore the effects of GLYCTK2 inhibition on GBM cell survival and metabolism under different nutrient conditions.
  • Identifying the upstream regulators of ERK1 and the downstream effectors of GLYCTK2 phosphorylation could provide new avenues for treatment.
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