Coppola, Laura (2025) N⁶-Isopentenyladenosine Disrupts Energy Metabolism in Glioblastoma. [Tesi di dottorato]

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Abstract

Glioblastoma (GBM) is the most aggressive primary brain tumor, characterized by high invasiveness, metabolic plasticity, and resistance to conventional therapies. In this work of thesis, it was investigated the anticancer activity of N⁶-isopentenyladenosine (iPA), a naturally occurring modified adenosine with pleiotropic effects, focusing on its impact on GBM energy metabolism. In the first part of the project, we showed that iPA impairs mitochondrial activity in GBM cell lines and primary cultures by modulating EGFR signaling and PUMA intracellular localization. Specifically, iPA prevented EGFR/EGFRvIII mitochondrial translocation by inhibiting Y845 phosphorylation, allowing PUMA to interact with mitochondria and trigger cell death. OCR analysis confirmed reduced basal respiration, ATP production, and maximal respiratory capacity upon treatment. In the second part, we showed that iPA suppresses aerobic glycolysis in GBM cells in a PKM2-dependent manner. ECAR analysis revealed decreased glycolytic activity and capacity, an event that was accompanied by reduced ATP and lactate production. iPA treatment downregulated PKM2 expression via inhibition of the IKKβ-NF-κB pathway. Taken together, these findings highlight the dual action of iPA on pyruvate metabolism, through inhibition of both mitochondrial metabolism and glycolysis, eventually impairing GBM bioenergetics. By focusing on EGFR signaling, PUMA activity, and PKM2 regulation, iPA emerges as a promising candidate for glioblastoma therapy, with potential to overcome metabolic adaptability, one of the main causes of treatment resistance.

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