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Glioblastoma Cells Counteract PARP Inhibition through Pro-Survival Induction of Lipid Droplets Synthesis and Utilization

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.

Publication metadata

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


DOI: 10.3390/cancers14030726


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Funder referenceFunder name
RTICC RD12/0036/0026
SAF2015- 70520- R
P12- CTS-383
r ISCIII CB16/12/00421