Détail du document
Identifiant
oai:HAL:inserm-03920600v1
Sujet
hepatocellular carcinoma hepatoblastoma lipotoxicity peridroplet mitochondria [SDV]Life Sciences [q-bio] [SDV.BBM]Life Sciences [q-bio]/Bio... [SDV.MHEP]Life Sciences [q-bio]/Hu... [SDV.MHEP.HEG]Life Sciences [q-bio... [SDV.CAN]Life Sciences [q-bio]/Can...Auteur
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, AksamLangue
enEditeur
HAL CCSD;MDPI
Catégorie
sciences : sciences du vivant
Année
2023
Date de référencement
07/12/2023
Mots clés
cancer cell pcsk9 sciences metabolic [sdvRésumé
International audience; 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.
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, 2023, Rewiring Lipid Metabolism by Targeting PCSK9 and HMGCR to Treat Liver Cancer, HAL CCSD;MDPI
