Non Canonical Roles of the Metabolic Enzymes PKM2, ENO1 and GAPDH as Drivers that Facilitate the Adaptation of Glioblastoma Cells to Stress, Promoting Malignant Progression.

Glioblastoma Multiforme (GBM) is an aggressive, treatment-resistant brain tumor that uses metabolic plasticity to support its survival and progression. This paper explores how the glycolytic enzymes PKM2, ENO1 and GAPDH take on non canonical functions outside of its primary metabolic role in glycolysis in GBM cells. PKM2 enters the nucleus to activate transcription factors like HIF-1 alpha which drive the expression of genes involved in proliferation, angiogenesis and glucose metabolism. ENO1 promotes the activation of the P13K/ Akt pathway and supports immune evasion by suppressing MHC class 1 expression and supporting polarisation of M2-like macrophages. GAPDH, another glycolytic enzyme, also responds to stress by moving into the nucleus where it regulates the activity of a protein p53 and sometimes is involved in acetylation though interactions with p300 CBP which in turn influences both cell cycle arrest and apoptosis. Together these enzymes help the tumour adapt to stress in the harsh tumour microenvironment and maintain its aggressive behaviour. Their functions show how metabolism and gene regulation are interconnected in GBM and suggest that targeting these moonlighting roles may offer new therapeutic strategies that show promise.