Targeting PCSK9 in Liver Cancer Cells Triggers Metabolic Exhaustion and Cell Death by Ferroptosis
| dc.rights.license | open | en_US |
| hal.structure.identifier | BoRdeaux Institute in onCology [Inserm U1312 - BRIC] | |
| dc.contributor.author | ALANNAN, Malak | |
| hal.structure.identifier | BoRdeaux Institute in onCology [Inserm U1312 - BRIC] | |
| dc.contributor.author | FATROUNI, Hala
IDREF: 256973717 | |
| hal.structure.identifier | BoRdeaux Institute in onCology [Inserm U1312 - BRIC] | |
| dc.contributor.author | TRÉZÉGUET, Véronique | |
| hal.structure.identifier | Laboratoire de biogenèse membranaire [LBM] | |
| dc.contributor.author | DITTRICH-DOMERGUE, Franziska | |
| hal.structure.identifier | Laboratoire de biogenèse membranaire [LBM] | |
| dc.contributor.author | MOREAU, Patrick
IDREF: 058610723 | |
| hal.structure.identifier | BoRdeaux Institute in onCology [Inserm U1312 - BRIC] | |
| dc.contributor.author | SIEGFRIED, Géraldine | |
| hal.structure.identifier | BoRdeaux Institute in onCology [Inserm U1312 - BRIC] | |
| dc.contributor.author | LIET, Benjamin | |
| hal.structure.identifier | BoRdeaux Institute in onCology [Inserm U1312 - BRIC] | |
| dc.contributor.author | KHATIB, Abdel-Majid | |
| hal.structure.identifier | BoRdeaux Institute in onCology [Inserm U1312 - BRIC] | |
| dc.contributor.author | GROSSET, Christophe | |
| hal.structure.identifier | الجامعة اللبنانية [بيروت] = Lebanese University [Beirut] = Université libanaise [Beyrouth] [LU / ULB] | |
| dc.contributor.author | BADRAN, Bassam | |
| hal.structure.identifier | الجامعة اللبنانية [بيروت] = Lebanese University [Beirut] = Université libanaise [Beyrouth] [LU / ULB] | |
| dc.contributor.author | FAYYAD-KAZAN, Hussein | |
| hal.structure.identifier | BoRdeaux Institute in onCology [Inserm U1312 - BRIC] | |
| dc.contributor.author | MERCHED, Aksam | |
| dc.date.accessioned | 2024-05-10T08:48:17Z | |
| dc.date.available | 2024-05-10T08:48:17Z | |
| dc.date.issued | 2023-01 | |
| dc.identifier.issn | 2073-4409 | en_US |
| dc.identifier.uri | https://oskar-bordeaux.fr/handle/20.500.12278/199735 | |
| dc.description.abstractEn | Deregulated lipid metabolism is a common feature of liver cancers needed to sustain tumor cell growth and survival. We aim at taking advantage of this vulnerability and rewiring the oncogenic metabolic hub by targeting the key metabolic player pro-protein convertase subtilisin/kexin type 9 (PCSK9). We assessed the effect of PCSK9 inhibition using the three hepatoma cell lines Huh6, Huh7 and HepG2 and validated the results using the zebrafish in vivo model. PCSK9 deficiency led to strong inhibition of cell proliferation in all cell lines. At the lipid metabolic level, PCSK9 inhibition was translated by an increase in intracellular neutral lipids, phospholipids and polyunsaturated fatty acids as well as a higher accumulation of lipid hydroperoxide. Molecular signaling analysis involved the disruption of the sequestome 1/Kelch-like ECH-associated protein 1/nuclear factor erythroid 2-related factor 2 (p62/Keap1/Nrf2) antioxidative axis, leading to ferroptosis, for which morphological features were confirmed by electron and confocal microscopies. The anti-tumoral effects of PCSK9 deficiency were validated using xenograft experiments in zebrafish. The inhibition of PCSK9 was effective in disrupting the oncometabolic process, inducing metabolic exhaustion and enhancing the vulnerability of cancer cells to iron-triggered lipid peroxidation. We provide strong evidence supporting the drug repositioning of anti-PCSK9 approaches to treat liver cancers. | |
| dc.language.iso | EN | en_US |
| dc.subject.en | PCSK9 | |
| dc.subject.en | ferroptosis | |
| dc.subject.en | hepatocellular carcinoma | |
| dc.subject.en | hepatoblastoma | |
| dc.subject.en | lipid metabolism | |
| dc.title.en | Targeting PCSK9 in Liver Cancer Cells Triggers Metabolic Exhaustion and Cell Death by Ferroptosis | |
| dc.type | Article de revue | en_US |
| dc.identifier.doi | 10.3390/cells12010062 | en_US |
| dc.subject.hal | Sciences du Vivant [q-bio] | en_US |
| dc.subject.hal | Sciences du Vivant [q-bio]/Biochimie, Biologie Moléculaire/Biochimie [q-bio.BM] | en_US |
| dc.subject.hal | Sciences du Vivant [q-bio]/Médecine humaine et pathologie | en_US |
| dc.subject.hal | Sciences du Vivant [q-bio]/Médecine humaine et pathologie/Hépatologie et Gastroentérologie | en_US |
| dc.subject.hal | Sciences du Vivant [q-bio]/Cancer | en_US |
| bordeaux.journal | Cells | en_US |
| bordeaux.page | 62 | en_US |
| bordeaux.volume | 12 | en_US |
| bordeaux.hal.laboratories | Laboratoire de Biogenèse Membranaire (LBM) - UMR 5200 | en_US |
| bordeaux.issue | 1 | en_US |
| bordeaux.institution | Université de Bordeaux | en_US |
| bordeaux.institution | CNRS | en_US |
| bordeaux.peerReviewed | oui | en_US |
| bordeaux.inpress | non | en_US |
| bordeaux.import.source | hal | |
| hal.identifier | inserm-03920582 | |
| hal.version | 1 | |
| hal.popular | non | en_US |
| hal.audience | Internationale | en_US |
| hal.export | false | |
| workflow.import.source | hal | |
| dc.rights.cc | Pas de Licence CC | en_US |
| bordeaux.COinS | ctx_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.jtitle=Cells&rft.date=2023-01&rft.volume=12&rft.issue=1&rft.spage=62&rft.epage=62&rft.eissn=2073-4409&rft.issn=2073-4409&rft.au=ALANNAN,%20Malak&FATROUNI,%20Hala&TR%C3%89Z%C3%89GUET,%20V%C3%A9ronique&DITTRICH-DOMERGUE,%20Franziska&MOREAU,%20Patrick&rft.genre=article |
