Dukhande, V. | Search bioRxiv

bioRxiv2025

Mitochondrial Dysfunction and Senescence Accompany Glioblastoma Cell Death Triggered by a Putative Metabolic Inhibitor

Glioblastoma (GBM) is a fatal cancer with a dismal prognosis and a dire need for novel chemotherapeutics. Metabolic reprogramming is an established hallmark of cancer. In our previous study on GBM, we aimed at targeting the metabolic reprogramming of cancer by using stiripentol (STP), a putative lactate dehydrogenase (LDH) inhibitor and an FDA-approved anti-epileptic drug. However, the precise mechanism of STPs anti-cancer activity remains unclear. We aimed to elucidate the mechanism of action of STP in GBM to further develop STP as a therapeutic. We employed a multiomic approach followed by metabolic and cellular assays. STP treatment induced genetic and metabolic alterations in GBM cells. Inhibition of LDH by STP was moderate but not potent. The cellular changes were accompanied by an increase in reactive oxygen species, a decrease in mitochondrial membrane potential, and induction of senescence in GBM cells. Our research indicates that further research in senescence-inducing agents and novel LDH inhibitors can provide novel therapeutics for GBM.

pharmacology and toxicology↗

bioRxiv2019

Compartmentalized glycogenolysis regulates lung cancer transcription

The role of cellular metabolites in the direct control of signaling is an emerging and rapidly evolving field. Herein, we identify a key role for nuclear glycogen in epigenetic regulation through compartmentalized acetyl CoA production and histone acetylation. Nuclear glycogenolysis is dependent on ubiquitination and translocation of glycogen phosphorylase (GP) into the nucleus by malin, an E3 ubiquitin ligase. We developed an innovative in organello stable isotope tracer method coupled to mass spectrometry analysis to define the metabolic fate of nuclear glycogen. This work revealed that GP is required for nuclear glycogen degradation and subsequent glycolysis to generate substrates for histone acetylation. Inhibition of nuclear glycogenolysis is found to be particularly important in non-small cell lung cancer (NSCLC), as evident by increased nuclear glycogen accumulation and malin suppression in NSCLC. Re-introduction of malin in model NSCLC cell lines restores nuclear glycogenolysis, resulting in increased histone acetylation and transcriptional changes that delay cancer cell growth in vivo. This study uncovers a previously unknown role for glycogen metabolism in the nucleus and elucidates another way by which cellular metabolites control epigenetic regulation.

cancer biology↗