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

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 F., Badran, Bassam, Fayyad-Kazan, Hussein, Merched, Aksam J.·2022·Cancers
DOI 10.3390/cancers15010003PMC PMC9817797
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Abstract

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.

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Research works printed but not linked: 27

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Metadata

Authors
Alannan, M., Trézéguet, V., Amoêdo, N. D., Rossignol, R., Mahfouf, W., Rezvani, H. R., Dittrich-Domergue, F., Moreau, P., Lacomme, S., Gontier, E., Grosset, C. F., Badran, B., Fayyad-Kazan, H., & Merched, A. J.
Affiliations
  • Bordeaux Institute of Oncology (BRIC), INSERM U1312, University of Bordeaux, F-33000 Bordeaux, France
  • CELLOMET, Functional Genomics Center (CGFB), INSERM U1211, University of Bordeaux, F-33000 Bordeaux, France
  • Laboratoire de Biogenèse Membranaire, Centre National de la Recherche Scientifique (CNRS), UMR 5200, University of Bordeaux, F-33140 Villenave d’Ornon, France
  • CNRS, INSERM, Bordeaux Imaging Center (BIC), University of Bordeaux, UAR 3420, US 4, F-33000 Bordeaux, France
  • Laboratory of Cancer Biology and Molecular Immunology, Faculty of Sciences I, Lebanese University, Hadath, Beirut, Lebanon
ORCID
Venue
Cancers
Publisher
MDPI AG
Published
2022-12-20
Volume
15
Issue
1
Pages
3
ISSN
2072-6694
DOI
10.3390/cancers15010003
PMC
PMC9817797
Cited by
25
References
0
Language
en
Licence
creativecommons.org/licenses/by/4.0/ (vor)
Funders
  • Cassandra contre les Leucémies et Cancers Pédiatriques (OPE-2018-0144, RE-2021-1AD-F, DBI20131228566, N°2020-012)
  • les Récoltes de l’Espoir (OPE-2018-0144, RE-2021-1AD-F, DBI20131228566, N°2020-012)
  • Fondation pour la Recherche Médicale (OPE-2018-0144, RE-2021-1AD-F, DBI20131228566, N°2020-012)
  • PELICAN.resist project and the Région Nouvelle-Aquitaine (OPE-2018-0144, RE-2021-1AD-F, DBI20131228566, N°2020-012)

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