Iannucci, Rosa (2024) Control of metabolic rewiring and autophagic pathway in Glioblastoma by the E3-ubiquitin ligase Praja2. [Tesi di dottorato]

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Abstract

Glioblastoma multiforme (GBM) is the most malignant form of primary brain tumor, whose high recurrence rate and resistance to standard treatments demand an urgent need for novel therapeutic strategies. The ubiquitin-proteasome system (UPS) is an important control mechanism of cell growth, metabolism, and alterations of this circuitry are linked to the onset and progression of various human cancers, including GBM. Thus, the ubiquitin-proteasome system represents a potential target for GBM treatment. In this study, we found that levels of praja2, a RING E3 ligase, are markedly enhanced in primary GBM lesions expressing the wild-type isocitrate dehydrogenase 1 gene (IDH1) and it is involved in the regulation of cell growth and metabolism. By using biochemical assays, we identified the 5’AMP-activated protein kinase (AMPK1 and AMPK1) and Kinase Suppressor of Ras 2 (KSR2) as putative partners of praja2. In particular, praja2 binds to, ubiquitylates, and degrades KSR2 attenuating the activity of the downstream effector AMPK. As a consequence, cells undergo a metabolic switch from oxidative respiration to glycolytic pathway, supporting GBM proliferation. Since AMPK exerts a role in autophagy regulation, we have established a functional link between the two degradative systems. Indeed, we demonstrated that praja2 negatively regulates basal autophagy machinery by binding to and ubiquitinating components of the ULK1/FIP200/ATG13 complex. Finally, we used transferrin-targeted self-assembling nanoparticles (SANPs) to deliver inhibitory RNA molecules targeting praja2 into the brain, observing a reduction in tumor growth and an increase in the survival rate of treated mice. Altogether, our findings identify praja2 as an essential regulator of cancer cell metabolism, and as a potential therapeutic target for GBM treatment.

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