Journal
FRONTIERS IN ONCOLOGY
Volume 12, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fonc.2022.988872
Keywords
glioblastoma; fatty acid metabolism; lipotoxicity; SCD1; FADS2; tumor heterogeneity
Categories
Funding
- VIB
- iBOF
- EOS
- FWO
- Stichting tegen Kanker, Komoptegen Kanker
- EU-Innovative
- European Research Council
- FWO - Research Projects
- KU Leuven - FTBO
- King Baudouin Foundation
- Beug Foundation
- Stichting tegen Kanker
- Fonds Baillet Latour
- [771486]
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This study reveals that the chemotherapeutic agent temozolomide affects fatty acid synthesis and desaturation in newly diagnosed glioblastoma, but this response is blunted in recurring glioblastoma. Furthermore, disrupting cellular fatty acid homeostasis and accumulating saturated fatty acids synergizes with temozolomide treatment, enhancing its efficacy.
Glioblastoma is a highly lethal grade of astrocytoma with very low median survival. Despite extensive efforts, there is still a lack of alternatives that might improve these prospects. We uncovered that the chemotherapeutic agent temozolomide impinges on fatty acid synthesis and desaturation in newly diagnosed glioblastoma. This response is, however, blunted in recurring glioblastoma from the same patient. Further, we describe that disrupting cellular fatty acid homeostasis in favor of accumulation of saturated fatty acids such as palmitate synergizes with temozolomide treatment. Pharmacological inhibition of SCD and/or FADS2 allows palmitate accumulation and thus greatly augments temozolomide efficacy. This effect was independent of common GBM prognostic factors and was effective against cancer cells from recurring glioblastoma. In summary, we provide evidence that intracellular accumulation of saturated fatty acids in conjunction with temozolomide based chemotherapy induces death in glioblastoma cells derived from patients.
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