title: Next-generation proteasome inhibitor oprozomib synergizes with modulators of the unfolded protein response to suppress hepatocellular carcinoma.
abstract: Hepatocellular carcinoma (HCC) responds poorly to conventional systemic therapies. The first-in-class proteasome inhibitor bortezomib has been approved in clinical use for hematologic malignancies and has shown modest activity in solid tumors, including HCC. However, a considerable proportion of patients fail to respond and experience important adverse events. Recently, the next-generation orally bioavailable irreversible proteasome inhibitor oprozomib was developed. Here, we assessed the efficacy of oprozomib and its effects on the unfolded protein response (UPR), a signaling cascade activated through the ATF6, PERK and IRE1 pathways by accumulation of unfolded proteins in the endoplasmic reticulum, in HCC. The effects of oprozomib and the role of the UPR were evaluated in HCC cell lines and in diethylnitrosamine-induced and xenograft mouse models for HCC. Oprozomib dose-dependently reduced the viability and proliferation of human HCC cells. Unexpectedly, oprozomib-treated cells displayed diminished cytoprotective ATF6-mediated signal transduction as well as unaltered PERK and IRE1 signaling. However, oprozomib increased pro-apoptotic UPR-mediated protein levels by prolonging their half-life, implying that the proteasome acts as a negative UPR regulator. Supplementary boosting of UPR activity synergistically improved the sensitivity to oprozomib via the PERK pathway. Oral oprozomib displayed significant antitumor effects in the orthotopic and xenograft models for HCC, and importantly, combining oprozomib with different UPR activators enhanced the antitumor efficacy by stimulating UPR-induced apoptosis without cumulative toxicity. In conclusion, next-generation proteasome inhibition by oprozomib results in dysregulated UPR activation in HCC. This finding can be exploited to enhance the antitumor efficacy by combining oprozomib with clinically applicable UPR activators.
authors.affiliation: Department of Hepatology and Gastroenterology, Ghent University, Ghent, Belgium.
authors.forename: Yves-Paul
authors.initials: YP
authors.lastname: Vandewynckel
authors.affiliation: Department of Hepatology and Gastroenterology, Ghent University, Ghent, Belgium.
authors.forename: Céline
authors.initials: C
authors.lastname: Coucke
authors.affiliation: Department of Hepatology and Gastroenterology, Ghent University, Ghent, Belgium.
authors.forename: Debby
authors.initials: D
authors.lastname: Laukens
authors.affiliation: Department of Hepatology and Gastroenterology, Ghent University, Ghent, Belgium.
authors.forename: Lindsey
authors.initials: L
authors.lastname: Devisscher
authors.affiliation: Department of Hepatology and Gastroenterology, Ghent University, Ghent, Belgium.
authors.forename: Annelies
authors.initials: A
authors.lastname: Paridaens
authors.affiliation: Department of Hepatology and Gastroenterology, Ghent University, Ghent, Belgium.
authors.forename: Eliene
authors.initials: E
authors.lastname: Bogaerts
authors.affiliation: Department of Hepatology and Gastroenterology, Ghent University, Ghent, Belgium.
authors.forename: Astrid
authors.initials: A
authors.lastname: Vandierendonck
authors.affiliation: Department of Hepatology and Gastroenterology, Ghent University, Ghent, Belgium.
authors.forename: Sarah
authors.initials: S
authors.lastname: Raevens
authors.affiliation: Department of Hepatology and Gastroenterology, Ghent University, Ghent, Belgium.
authors.forename: Xavier
authors.initials: X
authors.lastname: Verhelst
authors.affiliation: Department of Hepatology and Gastroenterology, Ghent University, Ghent, Belgium.
authors.forename: Christophe
authors.initials: C
authors.lastname: Van Steenkiste
authors.affiliation: Department of Pathology, Ghent University Hospital, Ghent, Belgium.
authors.forename: Louis
authors.initials: L
authors.lastname: Libbrecht
authors.affiliation: Department of Hepatology and Gastroenterology, Ghent University, Ghent, Belgium.
authors.forename: Anja
authors.initials: A
authors.lastname: Geerts
authors.affiliation: Department of Hepatology and Gastroenterology, Ghent University, Ghent, Belgium.
authors.forename: Hans
authors.initials: H
authors.lastname: Van Vlierberghe
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002934:Cinnamates / Q000494:pharmacology; D004357:Drug Synergism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy*; D051379:Mice; D019888:Nelfinavir / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D061988:Proteasome Inhibitors / Q000494:pharmacology; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology; D014415:Tunicamycin / Q000494:pharmacology; D056811:Unfolded Protein Response / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
chemical_list: D002934:Cinnamates; C554738:ONX 0912; D009842:Oligopeptides; D061988:Proteasome Inhibitors; C496827:salubrinal; D014415:Tunicamycin; D013890:Thiourea; D019888:Nelfinavir
keywords: endoplasmic reticulum; hepatocellular carcinoma; proteasome inhibitor; stress; unfolded protein response