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International Immunopharmacology Oct 2023Astrocytes are crucially involved in neuroinflammation. Activated astrocytes exhibit at least two phenotypes, A1 (neurotoxic) and A2 (neuroprotective). The A1 phenotype...
Astrocytes are crucially involved in neuroinflammation. Activated astrocytes exhibit at least two phenotypes, A1 (neurotoxic) and A2 (neuroprotective). The A1 phenotype is the major reactive astrocyte phenotype involved in aging and neurodegenerative diseases. Telmisartan, which is an antihypertensive agent, is a promising neuroprotective agent. This study aimed to investigate the effects of telmisartan on the phenotype of reactive astrocytes. Astrocytes were activated by culturing with the conditioned medium derived from lipopolysaccharide-stimulated microglia. This conditioned medium induced early, transient A2 astrocyte conversion (within 24 h) and late, sustained A1 conversion (beginning at 24 h and lasting up to 7 days), with a concomitant increase in the production of pro-inflammatory cytokines (interleukin [IL]-1β, tumor necrosis factor [TNF]α, and IL-6) and phosphorylation of nuclear factor-κB (NF-κB)/p65. Telmisartan treatment promoted and inhibited A2 and A1 conversion, respectively. Telmisartan reduced total and phosphorylated p65 protein levels. Losartan, a specific angiotensin II type-1 receptor (AT1R) blocker, did not influence the reactive state of astrocytes. Additionally, AT1R activation by angiotensin II did not induce the expression of pro-inflammatory cytokines and A1/A2 markers, indicating that the AT1R signaling pathway is not involved in the astrocyte-mediated inflammatory response. A peroxisome proliferator-activated receptor γ (PPARγ) antagonist reversed the effects of telmisartan. Moreover, telmisartan-induced p65 downregulation was reversed by the proteasome inhibitor MG132. These results indicate that telmisartan suppresses activated microglia-induced neurotoxic A1 astrocyte conversion through p65 degradation. Our findings contribute towards the elucidation of the anti-inflammatory activity of telmisartan in brain disorders.
Topics: Telmisartan; NF-kappa B; PPAR gamma; Astrocytes; Microglia; Angiotensin II; Culture Media, Conditioned; Angiotensin II Type 1 Receptor Blockers; Cytokines; Tumor Necrosis Factor-alpha
PubMed: 37544025
DOI: 10.1016/j.intimp.2023.110761 -
Journal of Experimental & Clinical... Sep 2023Tumors have evolved in various mechanisms to evade the immune system, hindering the antitumor immune response and facilitating tumor progression. Immunotherapy has... (Review)
Review
Tumors have evolved in various mechanisms to evade the immune system, hindering the antitumor immune response and facilitating tumor progression. Immunotherapy has become a potential treatment strategy specific to different cancer types by utilizing multifarious molecular mechanisms to enhance the immune response against tumors. Among these mechanisms, the ubiquitin-proteasome system (UPS) is a significant non-lysosomal pathway specific to protein degradation, regulated by deubiquitinating enzymes (DUBs) that counterbalance ubiquitin signaling. Ubiquitin-specific proteases (USPs), the largest DUB family with the strongest variety, play critical roles in modulating immune cell function, regulating immune response, and participating in antigen processing and presentation during tumor progression. According to recent studies, the expressions of some USP family members in tumor cells are involved in tumor immune escape and immune microenvironment. This review explores the potential of targeting USPs as a new approach for cancer immunotherapy, highlighting recent basic and preclinical studies investigating the applications of USP inhibitors. By providing insights into the structure and function of USPs in cancer immunity, this review aims at assisting in developing new therapeutic approaches for enhancing the immunotherapy efficacy.
Topics: Humans; Immunotherapy; Cytoplasm; Proteasome Endopeptidase Complex; Ubiquitin; Ubiquitin-Specific Proteases; Neoplasms
PubMed: 37658402
DOI: 10.1186/s13046-023-02805-y -
Cancer Research Aug 2023Liposarcoma is the most commonly occurring soft-tissue sarcoma and is frequently characterized by amplification of chromosome region 12q13-15 harboring the oncogenes...
UNLABELLED
Liposarcoma is the most commonly occurring soft-tissue sarcoma and is frequently characterized by amplification of chromosome region 12q13-15 harboring the oncogenes MDM2 and CDK4. This unique genetic profile makes liposarcoma an attractive candidate for targeted therapeutics. While CDK4/6 inhibitors are currently employed for treatment of several cancers, MDM2 inhibitors have yet to attain clinical approval. Here, we report the molecular characterization of the response of liposarcoma to the MDM2 inhibitor nutlin-3. Treatment with nutlin-3 led to upregulation of two nodes of the proteostasis network: the ribosome and the proteasome. CRISPR/Cas9 was used to perform a genome-wide loss of function screen that identified PSMD9, which encodes a proteasome subunit, as a regulator of response to nutlin-3. Accordingly, pharmacologic studies with a panel of proteasome inhibitors revealed strong combinatorial induction of apoptosis with nutlin-3. Mechanistic studies identified activation of the ATF4/CHOP stress response axis as a potential node of interaction between nutlin-3 and the proteasome inhibitor carfilzomib. CRISPR/Cas9 gene editing experiments confirmed that ATF4, CHOP, and the BH3-only protein, NOXA, are all required for nutlin-3 and carfilzomib-induced apoptosis. Furthermore, activation of the unfolded protein response using tunicamycin and thapsigargin was sufficient to activate the ATF4/CHOP stress response axis and sensitize to nutlin-3. Finally, cell line and patient-derived xenograft models demonstrated combinatorial effects of treatment with idasanutlin and carfilzomib on liposarcoma growth in vivo. Together, these data indicate that targeting of the proteasome could improve the efficacy of MDM2 inhibitors in liposarcoma.
SIGNIFICANCE
Targeting the proteasome in combination with MDM2 inhibition activates the ATF4/CHOP stress response axis to induce apoptosis in liposarcoma, providing a potential therapeutic approach for the most common soft-tissue sarcoma.
Topics: Humans; Proteasome Endopeptidase Complex; Proto-Oncogene Proteins c-mdm2; Tumor Suppressor Protein p53; Liposarcoma; Antineoplastic Agents; Proteasome Inhibitors; Apoptosis; Activating Transcription Factor 4
PubMed: 37205634
DOI: 10.1158/0008-5472.CAN-22-3173 -
Cancer Letters Jul 2024Ubiquitination and related cellular processes control a variety of aspects in human cell biology, and defects in these processes contribute to multiple illnesses. In... (Review)
Review
Ubiquitination and related cellular processes control a variety of aspects in human cell biology, and defects in these processes contribute to multiple illnesses. In recent decades, our knowledge about the pathological role of ubiquitination in lymphoid cancers and therapeutic strategies to target the modified ubiquitination system has evolved tremendously. Here we review the altered signalling mechanisms mediated by the aberrant expression of cancer-associated E2s/E3s and deubiquitinating enzymes (DUBs), which result in the hyperactivation of oncoproteins or the frequently allied downregulation of tumour suppressors. We discuss recent highlights pertaining to the several different therapeutic interventions which are currently being evaluated to effectively block abnormal ubiquitin-proteasome pathway and the use of heterobifunctional molecules which recruit the ubiquitination system to degrade or stabilize non-cognate substrates. This review aids in comprehension of ubiquitination aberrance in lymphoid cancers and current targeting strategies and elicits further investigations to deeply understand the link between cellular ubiquitination and lymphoid pathogenesis as well as to ameliorate corresponding treatment interventions.
Topics: Humans; Ubiquitination; Signal Transduction; Ubiquitin; Animals; Lymphoma; Molecular Targeted Therapy; Antineoplastic Agents; Proteasome Endopeptidase Complex; Deubiquitinating Enzymes
PubMed: 38795760
DOI: 10.1016/j.canlet.2024.216978 -
Nature Communications Feb 2024Aneuploidy, a deviation of the chromosome number from euploidy, is one of the hallmarks of cancer. High levels of aneuploidy are generally correlated with metastasis and...
Aneuploidy, a deviation of the chromosome number from euploidy, is one of the hallmarks of cancer. High levels of aneuploidy are generally correlated with metastasis and poor prognosis in cancer patients. However, the causality of aneuploidy in cancer metastasis remains to be explored. Here we demonstrate that teratomas derived from aneuploid murine embryonic stem cells (ESCs), but not from isogenic diploid ESCs, disseminated to multiple organs, for which no additional copy number variations were required. Notably, no cancer driver gene mutations were identified in any metastases. Aneuploid circulating teratoma cells were successfully isolated from peripheral blood and showed high capacities for migration and organ colonization. Single-cell RNA sequencing of aneuploid primary teratomas and metastases identified a unique cell population with high stemness that was absent in diploid ESCs-derived teratomas. Further investigation revealed that aneuploid cells displayed decreased proteasome activity and overactivated endoplasmic reticulum (ER) stress during differentiation, thereby restricting the degradation of proteins produced from extra chromosomes in the ESC state and causing differentiation deficiencies. Noticeably, both proteasome activator Oleuropein and ER stress inhibitor 4-PBA can effectively inhibit aneuploid teratoma metastasis.
Topics: Humans; Animals; Mice; DNA Copy Number Variations; Proteasome Endopeptidase Complex; Aneuploidy; Embryonic Stem Cells; Teratoma
PubMed: 38316790
DOI: 10.1038/s41467-024-45265-4 -
The Journal of Biological Chemistry Sep 2023The inhibitory mechanism of an intrinsically disordered proteasome inhibitor identified over 30 years ago has finally been revealed by cryo-electron microscopy by Hsu...
The inhibitory mechanism of an intrinsically disordered proteasome inhibitor identified over 30 years ago has finally been revealed by cryo-electron microscopy by Hsu et al. in a recent report in the Journal of Biological Chemistry. The structure, coupled with biochemical and cell-based experiments, resolves lingering questions about how the inhibitor achieves multisite inhibition of proteasomal protease activity, while raising several exciting new questions on the nature of proteasome subpopulations in the process.
Topics: Proteasome Inhibitors; Cryoelectron Microscopy; Proteasome Endopeptidase Complex
PubMed: 37562568
DOI: 10.1016/j.jbc.2023.105145 -
Gene Nov 2023The role of histone deacetylases (HDACs) in the tumor immune microenvironment of gynecologic tumors remains unexplored. We integrated data from The Cancer Genome Atlas...
The role of histone deacetylases (HDACs) in the tumor immune microenvironment of gynecologic tumors remains unexplored. We integrated data from The Cancer Genome Atlas and Human Protein Atlas to examine HDAC expression in breast, cervical, ovarian, and endometrial cancers. Elevated HDAC expression correlated with poor prognosis and highly malignant cancer subtypes. Gene Set Enrichment Analysis revealed positive associations between HDAC expression and tumor proliferation signature, while negative associations were found with tumor inflammation signature. Increased HDAC expression was linked to reduced infiltration of natural killer (NK), NKT, and CD8 T cells, along with negative associations with the expression of PSMB10, NKG7, CCL5, CD27, HLA-DQA1, and HLA-DQB1. In a murine 4T1 breast cancer model, treatment with suberoylanilide hydroxamic acid (SAHA; HDAC inhibitor) and PD-1 antibody significantly inhibited tumor growth and infiltration of CD3 and CD8 T cells. Real-time polymerase chain reaction revealed upregulated expressions of Psmb10, Nkg7, Ccl5, Cd8a, Cxcr6, and Cxcl9 genes, while Ctnnb1 and Myc genes were inhibited, indicating tumor suppression and immune microenvironment activation. Our study revealed that HDACs play tumor-promoting and immunosuppressive roles in gynecologic cancers, suggesting HDAC inhibitors as potential therapeutic agents for these cancers.
Topics: Female; Humans; Animals; Mice; Histone Deacetylases; Genital Neoplasms, Female; Hydroxamic Acids; CD8-Positive T-Lymphocytes; Vorinostat; Histone Deacetylase Inhibitors; Tumor Microenvironment; Membrane Proteins; Proteasome Endopeptidase Complex
PubMed: 37572797
DOI: 10.1016/j.gene.2023.147704 -
Science Advances Dec 2023We demonstrate that the Parkinson's VPS35[D620N] mutation alters the expression of ~220 lysosomal proteins and stimulates recruitment and phosphorylation of Rab proteins...
We demonstrate that the Parkinson's VPS35[D620N] mutation alters the expression of ~220 lysosomal proteins and stimulates recruitment and phosphorylation of Rab proteins at the lysosome. This recruits the phospho-Rab effector protein RILPL1 to the lysosome where it binds to the lysosomal integral membrane protein TMEM55B. We identify highly conserved regions of RILPL1 and TMEM55B that interact and design mutations that block binding. In mouse fibroblasts, brain, and lung, we demonstrate that the VPS35[D620N] mutation reduces RILPL1 levels, in a manner reversed by LRRK2 inhibition and proteasome inhibitors. Knockout of RILPL1 enhances phosphorylation of Rab substrates, and knockout of TMEM55B increases RILPL1 levels. The lysosomotropic agent LLOMe also induced LRRK2 kinase-mediated association of RILPL1 to the lysosome, but to a lower extent than the D620N mutation. Our study uncovers a pathway through which dysfunctional lysosomes resulting from the VPS35[D620N] mutation recruit and activate LRRK2 on the lysosomal surface, driving assembly of the RILPL1-TMEM55B complex.
Topics: Animals; Mice; Parkinson Disease; Mice, Knockout; Mutation; Lysosomes; Lysosomal Membrane Proteins
PubMed: 38091401
DOI: 10.1126/sciadv.adj1205 -
Cancer Dec 2023Patients with relapsed/refractory multiple myeloma (RRMM) have a high unmet treatment need. Belantamab mafodotin (belamaf), a first-in-class, B-cell maturation...
BACKGROUND
Patients with relapsed/refractory multiple myeloma (RRMM) have a high unmet treatment need. Belantamab mafodotin (belamaf), a first-in-class, B-cell maturation antigen-binding antibody-drug conjugate, eliminates myeloma cells through direct cell killing and an anti-myeloma immune response.
METHODS
DREAMM-2 (NCT03525678) was a phase 2, two-arm, open-label trial in patients with heavily pretreated RRMM who had three or more prior therapies, were refractory to an immunomodulatory agent and a proteasome inhibitor, and refractory or intolerant to an anti-CD38 monoclonal antibody. Belamaf was given at 2.5 or 3.4 mg/kg every 3 weeks. The primary end point was overall response rate (ORR); secondary end points included progression-free survival (PFS), overall survival (OS), safety, ocular symptoms, and health-related quality of life (HRQOL).
RESULTS
This final analysis (cutoff date, March 31, 2022), N = 223, with median follow-up of 12.5 and 13.8 months, demonstrated an ORR of 32% and 35%, median PFS of 2.8 and 3.9 months, and median OS of 15.3 and 14.0 months in the 2.5 mg/kg and 3.4 mg/kg cohorts, respectively. Median duration of response was 12.5 and 6.2 months. No new safety signals were observed; the most common Grade 3 and 4 adverse events were keratopathy (29% vs. 25%), thrombocytopenia (22% vs. 29%), and anemia (21% vs. 28%). HRQOL outcomes suggest that overall global health status/quality of life, physical and role functioning, and overall disease symptoms were maintained or improved during treatment.
CONCLUSIONS
This final analysis of DREAMM-2 confirms that in patients with triple-class refractory RRMM, single-agent belamaf results in durable and clinically meaningful responses with a manageable safety profile.
Topics: Humans; Multiple Myeloma; Quality of Life; Treatment Outcome; Antibodies, Monoclonal, Humanized
PubMed: 37622738
DOI: 10.1002/cncr.34987 -
Cancers Dec 2023Bortezomib (BTZ) is widely implemented in the treatment of multiple myeloma (MM). Its main mechanism of action is very well established. BTZ selectively and reversibly... (Review)
Review
Bortezomib (BTZ) is widely implemented in the treatment of multiple myeloma (MM). Its main mechanism of action is very well established. BTZ selectively and reversibly inhibits the 26S proteasome. More precisely, it interacts with the chymotryptic site of the 20S proteasome and therefore inhibits the degradation of proteins. This results in the intracellular accumulation of misfolded or otherwise defective proteins leading to growth inhibition and apoptosis. As well as interfering with the ubiquitin-proteasome complex, BTZ elicits various epigenetic alterations which contribute to its cytotoxic effects as well as to the development of BTZ resistance. In this review, we summarized the epigenetic alterations elicited by BTZ. We focused on modifications contributing to the mechanism of action, those mediating drug-resistance development, and epigenetic changes promoting the occurrence of peripheral neuropathy. In addition, there are therapeutic strategies which are specifically designed to target epigenetic changes. Herein, we also reviewed epigenetic agents which might enhance BTZ-related cytotoxicity or restore the sensitivity to BTZ of resistant clones. Finally, we highlighted putative future perspectives regarding the role of targeting epigenetic changes in patients exposed to BTZ.
PubMed: 38201512
DOI: 10.3390/cancers16010084