@misc{10481/110910,
year = {2022},
month = {1},
url = {https://hdl.handle.net/10481/110910},
abstract = {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.},
organization = {Junta de Andalucía (P10-CTS-0662, P12- CTS-383)},
organization = {Spanish Ministry of Economy and Competitiveness (SAF2012-40011-C02-01, SAF2015- 70520- R, RTI2018-098968-B-I00, RTICC RD12/0036/0026)},
organization = {CIBER Cancer ISCIII (CB16/12/00421)},
publisher = {MDPI},
keywords = {PARP inhibitors},
keywords = {Glioblastoma stem cells},
keywords = {Lipophagy},
title = {Glioblastoma Cells Counteract PARP Inhibition through Pro-Survival Induction of Lipid Droplets Synthesis and Utilization},
doi = {10.3390/cancers14030726},
author = {Majuelos-Melguizo, Jara and Rodríguez Vargas, José Manuel and Martínez-López, Nuria and Delgado Bellido, Daniel and Díaz García, José Ángel and Yuste, Víctor J and García-Macía, Marina and López, Laura M and Singh, Rajat and Oliver, Francisco Javier},
}