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

Autor: Alannan M; Bordeaux Institute of Oncology (BRIC), INSERM U1312, University of Bordeaux, F-33000 Bordeaux, France., Trézéguet V; Bordeaux Institute of Oncology (BRIC), INSERM U1312, University of Bordeaux, F-33000 Bordeaux, France., Amoêdo ND; CELLOMET, Functional Genomics Center (CGFB), INSERM U1211, University of Bordeaux, F-33000 Bordeaux, France., Rossignol R; CELLOMET, Functional Genomics Center (CGFB), INSERM U1211, University of Bordeaux, F-33000 Bordeaux, France., Mahfouf W; Bordeaux Institute of Oncology (BRIC), INSERM U1312, University of Bordeaux, F-33000 Bordeaux, France., Rezvani HR; Bordeaux Institute of Oncology (BRIC), INSERM U1312, University of Bordeaux, F-33000 Bordeaux, France., Dittrich-Domergue F; Laboratoire de Biogenèse Membranaire, Centre National de la Recherche Scientifique (CNRS), UMR 5200, University of Bordeaux, F-33140 Villenave d'Ornon, France., Moreau P; Laboratoire de Biogenèse Membranaire, Centre National de la Recherche Scientifique (CNRS), UMR 5200, University of Bordeaux, F-33140 Villenave d'Ornon, France., Lacomme S; CNRS, INSERM, Bordeaux Imaging Center (BIC), University of Bordeaux, UAR 3420, US 4, F-33000 Bordeaux, France., Gontier E; CNRS, INSERM, Bordeaux Imaging Center (BIC), University of Bordeaux, UAR 3420, US 4, F-33000 Bordeaux, France., Grosset CF; Bordeaux Institute of Oncology (BRIC), INSERM U1312, University of Bordeaux, F-33000 Bordeaux, France., Badran B; Laboratory of Cancer Biology and Molecular Immunology, Faculty of Sciences I, Lebanese University, Hadath, Beirut, Lebanon., Fayyad-Kazan H; Laboratory of Cancer Biology and Molecular Immunology, Faculty of Sciences I, Lebanese University, Hadath, Beirut, Lebanon., Merched AJ; Bordeaux Institute of Oncology (BRIC), INSERM U1312, University of Bordeaux, F-33000 Bordeaux, France.
Jazyk: angličtina
Zdroj: Cancers [Cancers (Basel)] 2022 Dec 20; Vol. 15 (1). Date of Electronic Publication: 2022 Dec 20.
DOI: 10.3390/cancers15010003
Abstrakt: 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.
Databáze: MEDLINE
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