title: Alpha-fetoprotein is a biomarker of unfolded protein response and altered proteostasis in hepatocellular carcinoma cells exposed to sorafenib.
abstract: Sorafenib is the treatment of reference for advanced hepatocellular carcinoma (HCC). A decrease in the serum levels of Alpha-fetoprotein (AFP) is reported to be the biological parameter that is best associated with disease control by sorafenib. In order to provide a biological rationale for the variations of AFP, we analyzed the various steps of AFP production in human HCC cell lines exposed to sorafenib. Sorafenib dramatically reduced the levels of AFP produced by HCC cells independently of its effect on cell viability. The mRNA levels of AFP decreased upon sorafenib treatment, while the AFP protein remained localized in the Golgi apparatus. Sorafenib activated the Regulated Inositol-Requiring Enzyme-1α (IRE-1α) and the PKR-like ER Kinase (PERK)-dependent arms of the Unfolded Protein Response (UPR). The inhibition of IRE-1α partially restored the mRNA levels of AFP upon treatment with sorafenib. The inhibition of both pathways partially prevented the drop in the production of AFP induced by sorafenib. The findings provide new insights on the regulation of AFP, and identify it as a biomarker suitable for the exploration of HCC cell proteostasis in the context of therapeutic targeting.
authors.affiliation: Service de Biochimie, Centre de Biologie Humaine (CBH), CHU Amiens Sud, Amiens, France.
authors.forename: Aline
authors.initials: A
authors.lastname: Houessinon
authors.affiliation: Service de Biochimie, Centre de Biologie Humaine (CBH), CHU Amiens Sud, Amiens, France.
authors.forename: Albane
authors.initials: A
authors.lastname: Gicquel
authors.affiliation: Service de Biochimie, Centre de Biologie Humaine (CBH), CHU Amiens Sud, Amiens, France.
authors.forename: Flora
authors.initials: F
authors.lastname: Bochereau
authors.affiliation: Service de Biochimie, Centre de Biologie Humaine (CBH), CHU Amiens Sud, Amiens, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Louandre
authors.affiliation: Service de Biochimie, Centre de Biologie Humaine (CBH), CHU Amiens Sud, Amiens, France.
authors.forename: Rémy
authors.initials: R
authors.lastname: Nyga
authors.affiliation: Service de Biochimie, Centre de Biologie Humaine (CBH), CHU Amiens Sud, Amiens, France; EA4666, Université de Picardie Jules Verne (UPJV), Amiens, France.
authors.forename: Corinne
authors.initials: C
authors.lastname: Godin
authors.affiliation: Service de Biochimie, Centre de Biologie Humaine (CBH), CHU Amiens Sud, Amiens, France.
authors.forename: James
authors.initials: J
authors.lastname: Degonville
authors.affiliation: Service de Biochimie, Centre de Biologie Humaine (CBH), CHU Amiens Sud, Amiens, France.
authors.forename: Emma
authors.initials: E
authors.lastname: Fournier
authors.affiliation: Service de Biochimie, Centre de Biologie Humaine (CBH), CHU Amiens Sud, Amiens, France.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Saidak
authors.affiliation: Université de Lille, Lille, France; UMR8161 CNRS, Lille, France; Institut Pasteur de Lille, Lille, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Drullion
authors.affiliation: EA4666, Université de Picardie Jules Verne (UPJV), Amiens, France.
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Barbare
authors.affiliation: EA4666, Université de Picardie Jules Verne (UPJV), Amiens, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Chauffert
authors.affiliation: EA4294, Université de Picardie Jules Verne (UPJV), Amiens, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: François
authors.affiliation: Université de Lille, Lille, France; UMR8161 CNRS, Lille, France; Institut Pasteur de Lille, Lille, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Pluquet
authors.affiliation: Service de Biochimie, Centre de Biologie Humaine (CBH), CHU Amiens Sud, Amiens, France; EA4666, Université de Picardie Jules Verne (UPJV), Amiens, France. Electronic address: Galmiche.Antoine@chu-amiens.fr.
authors.forename: Antoine
authors.initials: A
authors.lastname: Galmiche
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D015415:Biomarkers; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000502:physiology; D006706:Homeostasis; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D011506:Proteins / Q000378:metabolism*; D000071701:Regulatory Factor X Transcription Factors; D000077157:Sorafenib; D014157:Transcription Factors / Q000502:physiology; D056811:Unfolded Protein Response; D000509:alpha-Fetoproteins / Q000032:analysis* / Q000096:biosynthesis
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D004268:DNA-Binding Proteins; D010671:Phenylurea Compounds; D011506:Proteins; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000509:alpha-Fetoproteins; D009536:Niacinamide; D000077157:Sorafenib
keywords: Alpha-fetoprotein; Hepatocellular carcinoma; Proteostasis; Sorafenib; Unfolded Protein Response (UPR)