Next-generation proteasome inhibitor oprozomib synergizes with modulators of the unfolded protein response to suppress hepatocellular carcinoma
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Yves-Paul Vandewynckel1, Céline Coucke1, Debby Laukens1, Lindsey Devisscher1, Annelies Paridaens1, Eliene Bogaerts1, Astrid Vandierendonck1, Sarah Raevens1, Xavier Verhelst1, Christophe Van Steenkiste1, Louis Libbrecht2, Anja Geerts1, Hans Van Vlierberghe1
1Department of Hepatology and Gastroenterology, Ghent University, Ghent, Belgium
2Department of Pathology, Ghent University Hospital, Ghent, Belgium
Hans Van Vlierberghe, email: [email protected]
Keywords: hepatocellular carcinoma, endoplasmic reticulum, stress, unfolded protein response, proteasome inhibitor
Received: November 26, 2015 Accepted: March 31, 2016 Published: May 07, 2016
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.
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