Purine metabolism rewiring improves glioblastoma susceptibility to temozolomide treatment
Simona D’Aprile, Simona Denaro, Filippo Torrisi, Lucia Longhitano, Sebastiano Giallongo, Cesarina Giallongo, Vittorio Bontempi, Claudio Bucolo, Filippo Drago, Marina Mione, Giovanni Li Volti, Maja Potokar, Jernej Jorgačevski, Robert Zorec, Daniele Tibullo, Angela Maria Amorini, Nunzio Vicario, Rosalba Parenti
Abstract
Glioblastoma (GBM) is among the deadliest cancers, characterized by poor prognosis and median survival of 12-15 months post-diagnosis. Despite aggressive therapeutic regimens, GBM treatment is still an unmet clinical need due to heterogeneity, recurrencies, and resistance. Metabolic reshaping is emerging as a critical mechanism supporting cell proliferation and sustaining chemoresistance. In this study, we explored metabolic changes induced by chemotherapy in temozolomide (TMZ)-sensitive and TMZ-resistant GBM cell lines. We found that purine levels were altered in sensitive versus resistant GBM cells, highlighting a critical role of guanosine and inosine metabolism. By using a mesenchymal-like GBM zebrafish model, we uncovered dysregulated pathways involved in purine metabolism, with a downregulation of catabolic processes. Our data indicate that combined treatment with TMZ plus guanosine and inosine increased cytotoxicity, enhancing chemotherapy effectiveness in TMZ-resistant cells. These effects correlated with alterations in mitochondrial dynamics and activity. Specifically, the combinatorial effectiveness of TMZ with guanosine and inosine was linked to Mitofusin-2 overexpression, enhancing mitochondrial fusion, typically associated with a better prognosis. Therefore, our findings suggest that purine metabolism is involved in the metabolic rewiring of TMZ-resistant cells, suggesting guanosine and inosine as potential adjuvant treatments to improve the cytotoxicity effects of chemotherapy in resistant GBM.