2023-08-08·Clinical science (London, England : 1979)
ONX0914 inhibition of immunoproteasome subunit LMP7 ameliorates diabetic cardiomyopathy via restraining endothelial-mesenchymal transition.
作者: Mengwen Wang ; Yujian Liu ; Lei Dai ; Xiaodan Zhong ; Wenjun Zhang ; Yang Xie ; Hesong Zeng ; Hongjie Wang
Diabetic cardiomyopathy (DCM) is a chronic metabolic disease with few effective therapeutic options. Immunoproteasome is an inducible proteasome that plays an important role in the regulation of many cardiovascular diseases, while its role in DCM remains under discussion. This study aims to demonstrate whether inhibiting immunoproteasome subunit LMP7 could alleviate DCM. Here, we established a type I mouse model by streptozotocin (STZ) in 8-week-old male wild-type C57BL/6J mice. We found that immunoproteasome subunit LMP7 was overexpressed in the heart of diabetic mice, while inhibiting LMP7 with pharmacological inhibitor ONX0914 significantly alleviated myocardial fibrosis and improved cardiac function. Besides, compared to diabetic mice, ONX0914 treatment reduced protein levels of mesenchymal markers (Vimentin, alpha-smooth muscle actin, and SM22α) and increased endothelial markers (VE-cadherin and CD31). In TGFβ1 stimulated HUVECs, we also observed that ONX0914 could inhibit endothelial-mesenchymal transition (EndMT). Mechanistically, we prove that ONX0914 could regulate autophagy activity both in vivo and vitro. Meanwhile, the protective effect of ONX0914 on TGFβ1 stimulated HUVECs could be abolished by 3-Methyladenine (3MA) or Hydroxychloroquine (CQ). All in all, our data highlight that inhibition of LMP7 with ONX0914 could ameliorate EndMT in diabetic mouse hearts at least in part via autophagy activation. Thus, LMP7 may be a potential therapeutic target for the DCM.
2023-06-01·Journal of cancer research and clinical oncology
Gastric cancer cell types display distinct proteasome/immunoproteasome patterns associated with migration and resistance to proteasome inhibitors.
Gastric cancers (GC) display histological and molecular differences. This heterogeneity has limited the development of new therapeutic strategies which requires the identification of the molecular players involved in GC pathogenesis and the investigation of their responsiveness to drugs. Several proteasome subunits have been identified as prognostic markers in GC and their role studied by gene knockdown. However, proteasomes are multi-subunit protein complexes co-existing in multiple forms with distinct activity/specificity and ability to change in response to inhibitors. Information on the role of different proteasome particles in cancer and their relevance as therapeutic targets is limited.
Based on this evidence, subunit assembly into proteasome complexes and activity were investigated by native PAGE followed by immunoblotting, and by using fluorogenic substrates, respectively.
Here we show that GC cell lines with epithelial and/or diffuse Lauren's histotype express different levels of immunoproteasome subunits and equal amounts of constitutive counterparts. Immunoproteasome subunits were highly expressed and preferentially assembled into 19S capped complexes in diffuse-type cells, where most of the activity was catalyzed by the 26S and 30S particles. In epithelial cells, activity appeared equally distributed between 19S- and 11S-capped proteolytic particles. This proteasome pattern was associated with higher resistance of diffuse-type cells to proteasome inhibition. Immunoproteasome inhibition by ONX 0914 did not influence cell viability but affected metastatic cell migration.
These results suggest that pharmacological inhibition of the immunoproteasome may be useful in treating metastatic gastric cancers.
2023-05-03·International journal of molecular sciences
Chronic Administration of Non-Constitutive Proteasome Inhibitor Modulates Long-Term Potentiation and Glutamate Signaling-Related Gene Expression in Murine Hippocampus.
作者: Alexander Maltsev ; Sergei Funikov ; Alexander Rezvykh ; Ekaterina Teterina ; Vladimir Nebogatikov ; Alexander Burov ; Natalia Bal ; Aleksey Ustyugov ; Vadim Karpov ; Alexey Morozov
Proteasomes degrade most intracellular proteins. Several different forms of proteasomes are known. Little is known about the role of specific proteasome forms in the central nervous system (CNS). Inhibitors targeting different proteasome forms are used in clinical practice and were shown to modulate long-term potentiation (LTP) in hippocampal slices of untreated animals. Here, to address the role of non-constitutive proteasomes in hippocampal synaptic plasticity and reveal the consequences of their continuous inhibition, we studied the effect of chronic administration of the non-constitutive proteasome inhibitor ONX-0914 on the LTP induced by two different protocols: tetanic stimulation and theta-burst stimulation (TBS). Both the tetanus- and TBS-evoked potentiation contribute to the different forms of hippocampal-dependent memory and learning. Field-excitatory postsynaptic potentials (fEPSPs) in hippocampal slices from control animals and animals treated with DMSO or ONX-0914 were compared. LTP induced by the TBS was not affected by ONX-0914 administration; however, chronic injections of ONX-0914 led to a decrease in fEPSP slopes after tetanic stimulation. The observed effects correlated with differential expression of genes involved in synaptic plasticity, glutaminergic synapse, and synaptic signaling. Obtained results indicate that non-constitutive proteasomes are likely involved in the tetanus-evoked LTP, but not the LTP occurring after TBS, supporting the relevance and complexity of the role of specific proteasomes in synaptic plasticity, memory, and learning.