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.

Atf6α impacts cell number by influencing survival, death and proliferation

“…In addition to the canonical Atf6α downstream response leading to expanded ER proteosynthetic capacity, and the extensive evidence that Atf6α modulates cell survival, some studies have found that Atf6α action also influences the decision to enter the cell cycle. Some of the work implicating Atf6α in proliferation has been performed in cancer or cancer cell lines [117], [118], [119], [120], [121], [122]; other observations are in primary tissues such as pancreatic beta cells, ovarian cells, chondrocytes and cardiomyocytes [46], [92], [123], [124], [125]. In most cases, Atf6α activation increased cell cycle entry, whether as part of healthy tissue growth and adaptation or as a maladaptive response to disease.…”

“…Although the majority of studies investigating ATF6α in cancer cells have focused on oncogenic cell survival in the face of ER stress, there is evidence that ATF6α promotes proliferation as well. ATF6α, known to be a tumorigenic factor in hepatocellular carcinoma [130], drives proliferation and BrdU incorporation in hepatoma cells in a proteostasis-stress dependent manner [118]. Treating cells with a proteasome inhibitor oprozomib decreased proliferation by inhibiting regulated intramembrane proteolysis, thus reducing ATF6α cleavage and decreasing ATF6α target gene activation [118].…”

“…ATF6α, known to be a tumorigenic factor in hepatocellular carcinoma [130], drives proliferation and BrdU incorporation in hepatoma cells in a proteostasis-stress dependent manner [118]. Treating cells with a proteasome inhibitor oprozomib decreased proliferation by inhibiting regulated intramembrane proteolysis, thus reducing ATF6α cleavage and decreasing ATF6α target gene activation [118]. Similarly, the antiretroviral protease inhibitor nelfinavir was found to have anti-proliferative effects in prostate cancer and liposarcoma through an off-target inhibition of S1P/S2P activation of ATF6α [121], [122].…”

Activating transcription factor 6-dependent sestrin 2 induction ameliorates ER stress-mediated liver injury

“…Small chemical chaperones reducing ER stress are capable of ameliorating methionine and choline deficient diet-induced steatohepatitis [7], acetaminophen-induced hepatotoxicity [8], CCl 4 -induced liver fibrosis [9], ischemia-reperfusion-induced liver injury [10], and diethylnitrosamine-induced hepatic carcinogenesis [11]. Thus, it has been proposed the amelioration of ER stress is essential for maintaining liver homeostasis.…”

Targeting Non-Oncogene Addiction: Focus on Thyroid Cancer

“…It has been demonstrated that NFV acts as an inhibitor of HSP90 and causes unfolded protein response and ER stress [137]. Moreover, it synergizes with proteosome inhibitors to suppress cancer cells [138][139][140]. Interestingly, a recent study demonstrated that as NFV inhibits thyroid cancer cell proliferation and migration, it also induces DNA damage and sensitizes cells to anoikis, suggesting that it could be a new promising therapeutic agent for TC [26,141].…”