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Lookup NU author(s): Dr Nuria Martinez Lopez, Dr Marina Garcia Macia, Professor Rajat Singh
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2022 by the authors. Li- censee MDPI, Basel, Switzerland. Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor in adults. Poly (ADP-ribose) polymerase inhibitors (PARPi) represent a new class of anti-neoplastic drugs. In the current study, we have characterized the mechanism by which glioblastoma cells evade the effect of PARPi as antitumor agents. We have found that suppression of PARP activity exerts an anti-stemness effect and has a dual impact on autophagy, inducing its activation in the first 24 h (together with down-regulation of the pro-survival mTOR pathway) and preventing autophagosomes fusion to lysosomes at later time-points, in primary glioma cells. In parallel, PARPi triggered the synthesis of lipid droplets (LDs) through ACC-dependent activation of de novo fatty acids (FA) synthesis. Notably, inhibiting β-oxidation and blocking FA utilization, increased PARPiinduced glioma cell death while treatment with oleic acid (OA) prevented the antiglioma effect of PARPi. Moreover, LDs fuel glioma cells by inducing pro-survival lipid consumption as confirmed by quantitation of oxygen consumption rates using Seahorse respirometry in presence or absence of OA. In summary, we uncover a novel mechanism by which glioblastoma escapes to antitumor agents through metabolic reprogramming, inducing the synthesis and utilization of LDs as a prosurvival strategy in response to PARP inhibition.
Author(s): Majuelos-Melguizo J, Rodriguez-Vargas JM, Martinez-Lopez N, Delgado-Bellido D, Garcia-Diaz A, Yuste VJ, Garcia-Macia M, Lopez LM, Singh R, Oliver FJ
Publication type: Article
Publication status: Published
Journal: Cancers
Year: 2022
Volume: 14
Issue: 3
Print publication date: 01/02/2022
Online publication date: 30/01/2022
Acceptance date: 27/01/2022
Date deposited: 24/02/2022
ISSN (electronic): 2072-6694
Publisher: MDPI AG
URL: https://doi.org/10.3390/cancers14030726
DOI: 10.3390/cancers14030726
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