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| Pàgina inicial > Articles > Articles publicats > Glioblastoma Cells Counteract PARP Inhibition through Pro-Survival Induction of Lipid Droplets Synthesis and Utilization |
(Universidad Autónoma de Madrid. Departamento de Bioquímica) (Instituto de Parasitología y Biomedicina "López-Neyra") (Newcastle University. Institute for Cell and Molecular Biosciences) (Instituto de Parasitología y Biomedicina "López-Neyra") (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular) (Newcastle University. Institute of Cellular Medicine) (Instituto de Parasitología y Biomedicina "López-Neyra")| Data: | 2022 |
| Resum: | 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. |
| Ajuts: | 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 Instituto de Salud Carlos III RD12/0036/0026 Instituto de Salud Carlos III CB16/12/00421 |
| Drets: | 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.  |
| Llengua: | Anglès |
| Document: | Article ; recerca ; Versió publicada |
| Matèria: | Glioblastoma stem cells ; PARP inhibitors ; Lipophagy ; Lipid droplets ; Acyl-coA-carboxylase ; Metabolic adaptation |
| Publicat a: | Cancers, Vol. 14 Núm. 3 (january 2022) , ISSN 2072-6694 |
