The immunoproteasome inhibitor ONX‐0914 regulates inflammation and expression of contraction associated proteins in myometrium

Liong, Stella; Lim, Ratana; Nguyen-Ngo, Caitlyn; Barker, Gillian; Parkington, Helena C.; Lappas, Martha

doi:10.1002/eji.201747458

Cited by 10 publications

(7 citation statements)

References 53 publications

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“…The up‐regulation of the β5i/LMP7 subunit in acini and in macrophages might be linked to Toll‐like receptor pathways, as shown by other groups during infection and ethanol treatment 45,46 . In inflammatory diseases, several reports have associated β5i/LMP7 inhibition or deficiency with diminished cytokine production 47‐49 . Here, we show an opposite effect in which immunoproteasome deficiency correlates with an increased production of pro‐inflammatory cytokines where acini and macrophages are affected.…”

Section: Discussionsupporting

confidence: 65%

“…45,46 In inflammatory diseases, several reports have associated β5i/LMP7 inhibition or deficiency with diminished cytokine production. [47][48][49] Here, we show an opposite effect in which immunoproteasome deficiency correlates with an increased production of pro-inflammatory cytokines where acini and macrophages are affected. Over the last decade, various studies have found an association between oxidative stress and acinar cell damage, with neutrophils as the central player in this process.…”

Section: Discussionmentioning

confidence: 60%

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Immunoproteasome impairment via β5i/LMP7‐deletion leads to sustained pancreatic injury from experimental pancreatitis

Chama

Ebstein

Wiesrecker

et al. 2021

J Cellular Molecular Medi

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Acute pancreatitis, one of the most common gastrointestinal diseases, is an inflammation of the pancreas, thought to be primarily due to premature intra-acinar activation of digestive pancreatic zymogens. 1,2 Although most patients present with a mild form of the disease, about 20% develop severe pancreatitis associated with organ dysfunction, requiring intensive care. 3 The global incidence of acute pancreatitis has been reported by Xiao et. al. 4 to be 34 cases per 100 000 per year. Autodigestion of the pancreas by its own proteases leads to acinar cell injury and subsequently to a local and systemic inflammatory response. 5,6 Nevertheless,

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Section: Discussionsupporting

confidence: 65%

Section: Discussionmentioning

confidence: 60%

Immunoproteasome impairment via β5i/LMP7‐deletion leads to sustained pancreatic injury from experimental pancreatitis

Chama

Ebstein

Wiesrecker

et al. 2021

J Cellular Molecular Medi

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“…ONX-0914 displayed a higher inhibitory activity towards immunoproteasome β5i (IC50 5.7 nM) as compared to the constitutive proteasome β5c subunit (IC50 54 nM) [258]. ONX-0914 has been proven to be effective in the treatment of inflammatory disorders by specifically targeting immunoproteasome [164,259]. This indicates a therapeutic potential for anticancer therapies where the activity of immunoproteasome is upregulated.…”

Section: Onx-0914mentioning

confidence: 95%

Drug Development Targeting the Ubiquitin–Proteasome System (UPS) for the Treatment of Human Cancers

Zhang

Linder

Bazzaro

2020

Cancers

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Cancer cells are characterized by a higher rate of protein turnover and greater demand for protein homeostasis compared to normal cells. In this scenario, the ubiquitin-proteasome system (UPS), which is responsible for the degradation of over 80% of cellular proteins within mammalian cells, becomes vital to cancer cells, making the UPS a critical target for the discovery of novel cancer therapeutics. This review systematically categorizes all current reported small molecule inhibitors of the various essential components of the UPS, including ubiquitin-activating enzymes (E1s), ubiquitin-conjugating enzymes (E2s), ubiquitin ligases (E3s), the 20S proteasome catalytic core particle (20S CP) and the 19S proteasome regulatory particles (19S RP), as well as their mechanism/s of action and limitations. We also discuss the immunoproteasome which is considered as a prospective therapeutic target of the next generation of proteasome inhibitors in cancer therapies.Cancers 2020, 12, 902 2 of 34 core component of the nucleosome, which is critical for transcription and cell cycle, is recognized and linked by Lysine Residue 48 (K48) and further degraded by the proteasome [17,18]; DbpB (also named Y-box protein 1), a transcription factor, is reported to selectively recognize the Y-box promoter element. Studies showed that its terminal 105-amino-acid-long fragment is removed after a specific proteolytic cleavage by the proteasome complex [19,20]; NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) is located outside the nucleus and is reported to be involved in DNA transcription as well as cell survival [21,22]. The NF-κB p105 is the precursor of NF-κB p50. It is evident that NF-κB p105 is cleaved and selectively degraded at the C-terminus by proteasome, generating the active form of NF-κB p50 [23]. Products of UPS degradation can also be further degraded into single amino acids by aminopeptidases [24]. Aminopeptidases are the class of enzymes that catalyze the final steps in the ubiquitin-proteasome pathway by breaking down shorter peptides (<5 residues) into even smaller fragments [25]. Many, but not all, of aminopeptidases, are zinc metalloenzymes, such as leucine aminopeptidases (lAPs) and methionine aminopeptidases (metAPs) [26,27]. Studies showed that blocking the activity of the aminopeptidases by inhibitor of bestatin could generate a major accumulation of peptides which are ∼2-5 residues long [28].The 26S proteasome contains one/two 19S regulatory particles (19S RP) which mainly regulate the translocation of ubiquitinated proteins to the 20S CP and one 20S core particle (20S CP) in which proteolysis finally occurs [29,30]. In general, two main processes are associated with the process of degradation of proteins by the UPS: (1) tagging the to-be-degraded proteins by polyubiquitination (normally more than four ubiquitins), and (2) proteolytic degradation of the polyubiquitinated protein by the 26S proteasome complex [31,32]. Each step incorporates an intricate and complex spectrum of protein interaction...

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“…Our findings are in good congruence with data obtained previously using broad specificity proteasome inhibitors on A549 cells [ 31 ], human hepatocytes [ 32 ], prostate cancer cells [ 33 ], triple negative breast cancer cells [ 52 ], ovarian cancer cells [ 53 ], and lung epithelial and monocytic cells including THP-1 [ 54 ]. At the same time, decreased CXCL8 expression following ONX-0914 treatment was reported in human myometrial cells and tissues [ 55 ]. Though such discrepancy might be associated with differences in cellular origin and microenvironment.…”

Section: Discussionmentioning

confidence: 94%

Immunoproteasome Activity and Content Determine Hematopoietic Cell Sensitivity to ONX-0914 and to the Infection of Cells with Lentiviruses

Vagapova

Burov

Spasskaya

et al. 2021

Cells

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Proteasomes are intracellular structures responsible for protein degradation. The 20S proteasome is a core catalytic element of the proteasome assembly. Variations of catalytic subunits generate different forms of 20S proteasomes including immunoproteasomes (iPs), which are present mostly in the immune cells. Certain cells of the immune system are primary targets of retroviruses. It has been shown that several viral proteins directly affect proteasome functionality, while inhibition of proteasome activity with broad specificity proteasome inhibitors stimulates viral transduction. Here we specifically addressed the role of the immunoproteasomes during early stages of viral transduction and investigated the effects of specific immunoproteasome inhibition and activation prior to infection using a panel of cell lines. Inhibition of iPs in hematopoietic cells with immunoproteasome-specific inhibitor ONX-0914 resulted in increased infection by VSV-G pseudotyped lentiviruses. Moreover, a tendency for increased infection of cloned cells with endogenously decreased proteasome activity was revealed. Conversely, activation of iPs by IFN-γ markedly reduced the viral infectivity, which was rescued upon simultaneous immunoproteasome inhibition. Our results indicate that immunoproteasome activity might be determinative for the cellular antiretroviral resistance at least for the cells with high iP content. Finally, therapeutic application of immunoproteasome inhibitors might promote retroviral infection of cells in vivo.

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The immunoproteasome inhibitor ONX‐0914 regulates inflammation and expression of contraction associated proteins in myometrium

Cited by 10 publications

References 53 publications

Immunoproteasome impairment via β5i/LMP7‐deletion leads to sustained pancreatic injury from experimental pancreatitis

Immunoproteasome impairment via β5i/LMP7‐deletion leads to sustained pancreatic injury from experimental pancreatitis

Drug Development Targeting the Ubiquitin–Proteasome System (UPS) for the Treatment of Human Cancers

Immunoproteasome Activity and Content Determine Hematopoietic Cell Sensitivity to ONX-0914 and to the Infection of Cells with Lentiviruses

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