2026-04-17T00:46:38Zhttps://recercat.cat/oai/request

oai:recercat.cat:2072/4612822026-03-13T10:08:39Zcom_2072_98col_2072_378192

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 García-Díaz, Ángel Yuste, Victor José García-Macía, Marina López, Laura M. Singh, Rajat Oliver, F. J. Universitat Autònoma de Barcelona. Institut de Neurociències Glioblastoma stem cells PARP inhibitors Lipophagy Lipid droplets Acyl-coA-carboxylase Metabolic adaptation Glioblastoma multiforme (GBM) is the most common and deadly primary brain tumor in adults and one of the most aggressive cancers. The use of Poly ADP-Ribose Polymerase (PARP) inhibitors is being expanded as therapeutic alternative in multiple types of cancer beyond BRCA1/2 mutant breast and ovarian cancer. Here we have analyzed glioma cells' traits that limit the efficacy of PARPi as anti-glioma agents and we found that PARPi triggered the synthesis of lipid droplets (LDs) that fueled glioma cells by inducing pro-survival lipid consumption. Notably, blocking Fatty Acids utilization by inhibition of β-oxidation with etomoxir, increased PARPi-induced glioma cell death while treatment with oleic acid (OA) prevented the anti-glioma effect of PARPi. 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. 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. 2022 Article Ministerio de Economía y Competitividad SAF2012-40011-C02-01 Ministerio de Economía y Competitividad SAF2015-70520-R Agencia Estatal de Investigación RTI2018-098968-B-I00 Ministerio de Economía y Competitividad RD12/0036/0026 Ministerio de Economía y Competitividad CB16/12/00421 Cancers ; Vol. 14 Núm. 3 (january 2022) open access Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original. https://creativecommons.org/licenses/by/4.0/