Pharmacological Ascorbate Restrains Epithelial-Mesenchymal Transition and Invasion in Glioblastoma Cells via...

Glioblastoma (GBM) is highly invasive, and diffuse tumor cell migration into surrounding brain tissue remains a major obstacle to durable therapeutic control. Pharmacological ascorbate (P-AscH^-) exhibits anticancer activity through pro-oxidant mechanisms; however, its effects on GBM motility and invasion remain incompletely defined. Transcriptomic analyses revealed a strong association between glioma aggressiveness and gene programs governing migration and invasion. Here, we demonstrate that P-AscH^- markedly suppresses migration and invasion of GBM cells. These phenotypic effects are accompanied by coordinated repression of epithelial-mesenchymal transition (EMT) programs, characterized by reduced expression of mesenchymal markers (ZEB1, N-cadherin, Vimentin, Slug, and Twist1) and induction of the epithelial marker Claudin-1 at both transcriptional and protein levels. In parallel, P-AscH^- significantly downregulates invasion-associated matrix metalloproteinases MMP2 and MMP9 at the mRNA level. Mechanistically, catalase rescue experiments establish extracellular hydrogen peroxide as an essential mediator of P-AscH^--induced inhibition of GBM motility and EMT-associated gene and protein expression. In addition, P-AscH^- attenuates mTOR signaling, and combination with a dual mTORC1/2 inhibitor further reinforces suppression of migratory behavior and mesenchymal programs. Importantly, these phenotypic and molecular effects are conserved in a patient-derived glioblastoma model, underscoring translational relevance. Collectively, these findings identify extracellular hydrogen peroxide-driven redox signaling as a key mechanism by which pharmacological ascorbate suppresses EMT and invasive programs in GBM, providing mechanistic support for ongoing clinical evaluation and highlighting its potential utility as an invasion-targeted therapeutic strategy in GBM and other highly plastic malignancies.