Glioblastoma Cells Counteract PARP Inhibition through Pro-Survival Induction of Lipid Droplets Synthesis and Utilization Majuelos-Melguizo, Jara Rodríguez Vargas, José Manuel Martínez-López, Nuria Delgado Bellido, Daniel Díaz García, José Ángel Yuste, Víctor J García-Macía, Marina López, Laura M Singh, Rajat Oliver, Francisco Javier PARP inhibitors Glioblastoma stem cells Lipophagy This research was funded by Junta de Andalucía, Project of Excellence P10-CTS-0662, P12- CTS-383 to FJO, Spanish Ministry of Economy and Competitiveness SAF2012-40011-C02-01, SAF2015- 70520- R, RTI2018-098968-B-I00, RTICC RD12/0036/0026 and CIBER Cancer ISCIII CB16/12/00421 to FJO. 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 anti-tumor 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 PARPi-induced glioma cell death while treatment with oleic acid (OA) prevented the anti-glioma 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 anti-tumor agents through metabolic reprogramming, inducing the synthesis and utilization of LDs as a pro-survival strategy in response to PARP inhibition. 2026-02-12T09:28:21Z 2026-02-12T09:28:21Z 2022-01-30 journal article Majuelos-Melguizo J, Rodríguez-Vargas JM, Martínez-López N, Delgado-Bellido D, García-Díaz Á, Yuste VJ, García-Macía M, López LM, Singh R, Oliver FJ. (2022). Glioblastoma Cells Counteract PARP Inhibition through Pro-Survival Induction of Lipid Droplets Synthesis and Utilization. Cancers (Basel) Vol. 14 (3): 726. doi: 10.3390/cancers14030726 2072-6694 https://hdl.handle.net/10481/110910 10.3390/cancers14030726 eng http://creativecommons.org/licenses/by-nc-nd/4.0/ open access Attribution-NonCommercial-NoDerivatives 4.0 Internacional MDPI