title: The retinoblastoma (Rb) protein regulates ferroptosis induced by sorafenib in human hepatocellular carcinoma cells.
abstract: Sorafenib is the treatment of reference for advanced hepatocellular carcinoma (HCC), the most frequent form of primary liver tumour. The loss of function of the retinoblastoma (Rb) protein is an important event during liver carcinogenesis, but it is unclear whether the Rb status modulates the response of HCC cells to sorafenib. Here, we examined this question in HCC cells with reduced levels of Rb achieved through stable RNA interference. We show that HCC cells with reduced levels of Rb exhibit a two- to threefold increase in cell death induction upon exposure to sorafenib compared with controls. Sorafenib treatment of Balb/c nude mice that received tumour xenografts derived from HCC cells with reduced Rb levels resulted in complete tumour regression in 50% of the animals treated, compared with tumour stabilization in mice that received control cells. We show that, upon exposure to sorafenib, the Rb-negative status of HCC cells promotes the occurrence of ferroptosis, a form of oxidative necrosis. The findings highlight the role of Rb in the response of HCC cells to sorafenib and the regulation of ferroptosis.
authors.affiliation: Laboratoire de Biochimie, CHU Amiens, Amiens, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Louandre
authors.affiliation: EA4666, Université de Picardie Jules Verne, Amiens, France.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Marcq
authors.affiliation: EA4666, Université de Picardie Jules Verne, Amiens, France.
authors.forename: Hicham
authors.initials: H
authors.lastname: Bouhlal
authors.affiliation: Laboratoire de Biochimie, CHU Amiens, Amiens, France; EA4666, Université de Picardie Jules Verne, Amiens, France.
authors.forename: Emma
authors.initials: E
authors.lastname: Lachaier
authors.affiliation: Laboratoire de Biochimie, CHU Amiens, Amiens, France; EA4666, Université de Picardie Jules Verne, Amiens, France.
authors.forename: Corinne
authors.initials: C
authors.lastname: Godin
authors.affiliation: Laboratoire de Biochimie, CHU Amiens, Amiens, France.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Saidak
authors.affiliation: EA4294, Université de Picardie Jules Verne, Amiens, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: François
authors.affiliation: Service d'Anatomopathologie, CHU Amiens, Amiens, France.
authors.forename: Denis
authors.initials: D
authors.lastname: Chatelain
authors.affiliation: EA4666, Université de Picardie Jules Verne, Amiens, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Debuysscher
authors.affiliation: EA4666, Université de Picardie Jules Verne, Amiens, France.
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Barbare
authors.affiliation: EA4666, Université de Picardie Jules Verne, Amiens, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Chauffert
authors.affiliation: Laboratoire de Biochimie, CHU Amiens, Amiens, France; EA4666, Université de Picardie Jules Verne, Amiens, France. Electronic address: Galmiche.Antoine@chu-amiens.fr.
authors.forename: Antoine
authors.initials: A
authors.lastname: Galmiche
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009336:Necrosis; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects*; D010671:Phenylurea Compounds / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism*; D000077157:Sorafenib; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D017382:Reactive Oxygen Species; D016160:Retinoblastoma Protein; D009536:Niacinamide; D000077157:Sorafenib
keywords: Ferroptosis; Hepatocellular carcinoma; Rb; Sorafenib