ALANNAN, Malak; TRÉZÉGUET, Véronique; AMOÊDO, Nivea Dias; ROSSIGNOL, Rodrigue; MAHFOUF, Walid; REZVANI, Hamid Reza; DITTRICH-DOMERGUE, Franziska; MOREAU, Patrick; LACOMME, Sabrina; GONTIER, Etienne; GROSSET, Christophe; BADRAN, Bassam; FAYYAD-KAZAN, Hussein; MERCHED, Aksam

doi:10.3390/cancers15010003

BoRdeaux Institute in onCology [Inserm U1312 - BRIC]

TRÉZÉGUET, Véronique
BoRdeaux Institute in onCology [Inserm U1312 - BRIC]

AMOÊDO, Nivea Dias
Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) [U1211 INSERM/MRGM]
Cellomet [CHU Pellegrin, Bordeaux]

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Article de revue

Ce document a été publié dans

Cancers. 2023-01, vol. 15, n° 1, p. 3

Résumé en anglais

Alterations in lipid handling are an important hallmark in cancer. Our aim here is to target key metabolic enzymes to reshape the oncogenic lipid metabolism triggering irreversible cell breakdown. We targeted the key metabolic player proprotein convertase subtilisin/kexin type 9 (PCSK9) using a pharmacological inhibitor (R-IMPP) alone or in combination with 3-hydroxy 3-methylglutaryl-Coenzyme A reductase (HMGCR) inhibitor, simvastatin. We assessed the effect of these treatments using 3 hepatoma cell lines, Huh6, Huh7 and HepG2 and a tumor xenograft in chicken choriorallantoic membrane (CAM) model. PCSK9 deficiency led to dose-dependent inhibition of cell proliferation in all cell lines and a decrease in cell migration. Co-treatment with simvastatin presented synergetic anti-proliferative effects. At the metabolic level, mitochondrial respiration assays as well as the assessment of glucose and glutamine consumption showed higher metabolic adaptability and surge in the absence of PCSK9. Enhanced lipid uptake and biogenesis led to excessive accumulation of intracellular lipid droplets as revealed by electron microscopy and metabolic tracing. Using xenograft experiments in CAM model, we further demonstrated the effect of anti-PCSK9 treatment in reducing tumor aggressiveness. Targeting PCSK9 alone or in combination with statins deserves to be considered as a new therapeutic option in liver cancer clinical applications.< Réduire

Mots clés en anglais

hepatocellular carcinoma

hepatoblastoma

lipotoxicity

peridroplet mitochondria

URI

https://oskar-bordeaux.fr/handle/20.500.12278/199733

DOI

http://dx.doi.org/10.3390/cancers15010003

Unités de recherche

Laboratoire de Biogenèse Membranaire (LBM) - UMR 5200

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Rewiring Lipid Metabolism by Targeting PCSK9 and HMGCR to Treat Liver Cancer

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Résumé en anglais

Mots clés en anglais

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