title: Sorafenib-mediated targeting of the AAA⁺ ATPase p97/VCP leads to disruption of the secretory pathway, endoplasmic reticulum stress, and hepatocellular cancer cell death.
abstract: The molecular mechanisms and cellular targets of sorafenib, a multikinase inhibitor used for the treatment of hepatocellular carcinoma (HCC), remain to be fully characterized. Recent studies have shown that sorafenib induces tumor cell death through the activation of endoplasmic reticulum stress signaling and/or autophagy in various cellular models. Using liver cancer-derived cell lines, we specifically show that the IRE1 and phosphorylated extracellular signal-regulated kinase arms of the unfolded protein response (UPR) become activated upon sorafenib treatment, whereas the ATF6 arm is inhibited. Our results also reveal that sorafenib treatment causes disruption to the secretory pathway, as witnessed by the fragmentation of the Golgi apparatus and the induction of autophagy. On the basis of these observations, we tested the relevance of the AAA⁺ ATPase p97/VCP as a potential functional target of sorafenib. Our results show that p97/VCP tyrosine phosphorylation is prevented upon sorafenib treatment, and that this can be correlated with enhanced membrane association. Moreover, we show that DBeQ, a recently discovered inhibitor of p97/VCP, enhances sorafenib-mediated toxicity in cultured cells. Our data show a novel mechanism for sorafenib-mediated cell death in HCC, which depends on the integrity of the secretory pathway; and we identify p97/VCP phosphorylation as a potential target for improved sorafenib treatment efficacy in patients.
authors.affiliation: Institut National de la Santé et de la Recherche Medicale U1053, Bordeaux, France.
authors.forename: Ping
authors.initials: P
authors.lastname: Yi
authors.forename: Arisa
authors.initials: A
authors.lastname: Higa
authors.forename: Said
authors.initials: S
authors.lastname: Taouji
authors.forename: Mariana G
authors.initials: MG
authors.lastname: Bexiga
authors.forename: Esther
authors.initials: E
authors.lastname: Marza
authors.forename: Daniela
authors.initials: D
authors.lastname: Arma
authors.forename: Claire
authors.initials: C
authors.lastname: Castain
authors.forename: Brigitte
authors.initials: B
authors.lastname: Le Bail
authors.forename: Jeremy C
authors.initials: JC
authors.lastname: Simpson
authors.forename: Jean
authors.initials: J
authors.lastname: Rosenbaum
authors.forename: Charles
authors.initials: C
authors.lastname: Balabaud
authors.forename: Paulette
authors.initials: P
authors.lastname: Bioulac-Sage
authors.forename: Jean-Frédéric
authors.initials: JF
authors.lastname: Blanc
authors.forename: Eric
authors.initials: E
authors.lastname: Chevet
mesh_terms: D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D045744:Cell Line, Tumor; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D058990:Molecular Targeted Therapy; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D055571:Secretory Pathway / Q000187:drug effects; D000077157:Sorafenib
chemical_list: D000970:Antineoplastic Agents; C558357:N2,N4-dibenzylquinazoline-2,4-diamine; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D009536:Niacinamide; D000077157:Sorafenib; D020928:Mitogen-Activated Protein Kinases; D000251:Adenosine Triphosphatases