MG132

However, it effectively inhibited CD24 expression after treatment, and the effect that can be reversed with a proteasome inhibitor MG132. Importantly, it altered the immune environment within tumors and boosted the presence of immune cells that fight cancer including the infiltration increase of M1 macrophages and T lymphocytes in tumor tissues and the decrease of M2 macrophages. The research confirmed that erythromycin enhanced the anti-tumor immune response in HCC-bearing mice by reducing CD24 expression, providing a novel strategy for the clinical development of HCC treatments.

Further investigations elucidated that ABRAXAS2 degradation triggered the subsequent degradation of adjacent BRCC3, which in turn, hindered TNIP1/ABIN1 degradation, ultimately inhibiting NFKB/NF-κB (nuclear factor kappa B)-mediated inflammatory responses. This chain of events offers valuable insights into the NFKB activation by the K63-specific deubiquitinating role of BRISC, unveiling how bacteria manipulate ubiquitin regulation and selective autophagy within the BRISC network to inhibit the host's inflammatory response and thus dominate a pathogen-host tug-of-war.Abbreviations: 3-MA: 3-methyladenine; A/E: attaching and effacing; ATG7: autophagy related 7; BafA1: bafilomycin A1; BNIP3L/Nix: BCL2 interacting protein 3 like; BRISC: BRCC3 isopeptidase complex; Cas9: CRISPR-associated system 9; co-IP: co-immunoprecipitation; CQ: chloroquine; CRISPR: clustered regulatory interspaced short palindromic repeat; DAPI: 4',6-diamidino2-phenylindole; DMSO: dimethyl sulfoxide; DUB: deubiquitinating enzyme; E. coli: Escherichia coli; EHEC: enterohemorrhagic Escherichia coli; EPEC: enteropathogenic Escherichia coli; GFP: green fluorescent protein; LEE: locus of enterocyte effacement; MAP1LC3B/LC3: microtubule associated protein 1 light chain 3 beta; MG132: cbz-leu-leu-leucinal; MOI: multiplicity of infection; NBR1: NBR1 autophagy cargo receptor; NC: negative control; NFKB/NF-κB: nuclear factor kappa B; NH4Cl: ammonium chloride; OPTN: optineurin; SQSTM1/p62: sequestosome 1; sgRNAs: small guide RNAs; T3SS: type III secretion system; TNF: tumor necrosis factor; TOLLIP: toll interacting protein; TRAF: TNF receptor associated factor; TUBB: tubulin beta class I; WCL: whole cell lysate; WT: wide type.

Overall, MG132 was revealed to exert potent cytotoxic effects on ELT3 uterine leiomyoma cells by inducing ROS-mediated apoptosis and cell cycle arrest, and triggering autophagy. These findings suggest that MG132 provides a proof of concept for targeting the proteasome in uterine leiomyomas.

Furthermore, proteasomal inhibitor MG132 could block TYMS inhibition induced by Huachansu, and concomitant administration of protein synthesis inhibitor cycloheximide (CHX) with Huachansu could further suppress the protein level of TYMS, indicating that Huachansu promotes proteasome-dependent degradation of TYMS in liver cancer cells...5-Fluorouracil (5-FU) is a TYMS inhibitor, we also evaluate the effects of the combined treatment of Huachansu with 5-FU, the results show that interactions between Huachansu and 5-FU are synergistic or antagonistic. Thus, in clinical, attention should be paid to the dosage of Huachansu in combination with 5-FU. Huachansu inhibits the growth and induces DNA damage of human HCC cells through proteasome-dependent degradation of TYMS, bioactive bufadienolides are the material basis of down-regulation of TYMS induced by Huachansu.

Chemotherapy drug response models found five potential drugs, including all-trans retinoic acid, doxorubicin, etoposide, methotrexate and MG-132, were significantly associated with target genes in gene-panel. Molecular docking confirmed that potential drugs have good binding ability to target genes APP, GSTA4 and UCHL1, suggesting that the multi-gene panel is expected to provide assistance for drug resistance prediction and prognosis assessment and combination therapy in patients with anti-PD-1 resistant melanoma.

To assess the role of ERK signaling in PPN-induced melanogenesis regulation, PD98059, an ERK inhibitor, was used. Likewise, when Melan-A cells were treated with MG132, a proteasomal inhibitor, the reduced expression level of MITF and melanin content induced by piperine were restored. Consequently, PPN can be a potential candidate for application as a skin whitening agent or in formulations to mitigate hyperpigmentation.

In addition to tempol and silymarin, a mitochondrial permeability transition pore inhibitor, cyclosporine A, also alleviated the Zn-induced changes in animals...Besides, UPS inhibitor, MG132, enhanced Zn-induced UPS impairment, protein aggregation and mitochondrial dysfunction in differentiated cells. These results suggest that mitochondrial dysfunction triggers UPS impairment or vice versa that elevates α-Syn aggregation and consequent neuronal death. Furthermore, tempol and silymarin ameliorate the mitochondrial and UPS impairments and α-Syn aggregation thereby providing protection from Zn-induced neurotoxicity.

Furthermore, treatment with the proteasome inhibitor MG132 was found to attenuate KGF-induced K10 reduction, suggesting the involvement of the ubiquitin-proteasome system...However, TRIM21 overexpression decreased the sensitivity of FaDu cells to 5-fluorouracil, whereas TRIM21 knockdown or KGF administration significantly increased 5-fluorouracil sensitivity. Taken together, these findings highlight the intricate balance between protein stabilization and degradation orchestrated by KGF. This ubiquitination-mediated non-degradation mechanism of TRIM21 may provide novel therapeutic strategies for HPC and other cancers.

Our study reveals that DIAPH3 mRNA was modified in CRC cells by m1A methylation. Silencing DIAPH3 suppresses the migration and invasion of CRC cells, potentially through the proteasome-dependent degradation of downstream KRT19.

Besides, temozolomide resistance was associated with elevated proteasome activity that suppressed ER stress, which was restored upon inhibition of the proteasome with MG132. This boosted autophagosome nucleation, increased pro-death autophagy, and restored apoptosis in temozolomide-resistant glioblastoma cells. Finally, targeting PSMC2 provided a unique method for interrupting autophagy-mediated ER stress maintenance and temozolomide resistance in glioblastoma.

The SPOP-overexpression PC3 cells were treated with MG132 inhibitor, and the expression of FADD was detected by western blot...There may be a SPOP-FADD-NF-κB regulatory axis in PCa. SPOP facilitates the degradation of FADD, leading to a decrease in the activity of the NF-κB signaling pathway.

Deletion of HSP90α or HSP90β by CRISPR-Cas9 or inhibition of HSP90 activity by IPI-504 down-regulates RDH5 protein level, but not its mRNA expression, and this downregulation is restored by autophagic inhibitors (3-MA, CQ and Baf-A1) and siRNA of ATG5 or ATG7, but not by the proteasome inhibitor MG132. RDH5 is a novel client candidate of HSP90. The downregulation of RDH5 may be responsible for the nyctalopia side effect noted in cancer patients receiving HSP90 inhibitor treatment currently in the clinical trial.

WBP2 upregulation-initiated the chemoresistance to doxorubicin was reversed by exogenous ITCH, which was not affected by ITCH C830A mutant. In in vivo model, exogenous ITCH obstructed WBP2-mediated chemoresistance, which was destroyed by the proteasome inhibitor (MG132)...Our findings present how ITCH/WBP2 signaling functions to link the intricate AMOTL2/c-JUN signaling networks in chemoresistant BC cells. Targeting WBP2 combined with c-JUN inhibitors may be a potential option to overcome chemoresistance in breast cancer patients.

TRIM22 promoted KAT2A ubiquitination degradation to reduce H3K9ac enrichment levels in the GPX4 promoter region, and facilitated ferroptosis, thereby inhibiting HCC cell invasion and metastasis and in vivo growth and metastasis.

We further showed that FAK-I reduced DNMT3A expression in breast cancer cells and that treatment with the proteasome inhibitor MG132 prevented loss of DNTM3A protein stability...Immunostaining of 4T1 tumors showed FAK-I decreased DNMT3A, DNA methylation (5-methylcytosine, 5-mC), and increased DAB2 expression. Taken together, these data suggest that nuclear FAK-mediated regulation of DNMT3A can alter the epigenetic landscape and induce tumor suppressor gene expression.

These findings indicate that specific regulation of STAT3 was closely related with the cellular vulnerability to isoflurane via an antioxidative pathway.

We revealed a new regulatory effect of OA in CRC tumorigenesis via PPARγ-mediated Nur77 ubiquitin degradation.

Using cycloheximide, MG-132, and ubiquitination assays, we further demonstrate mechanistically that RSK1 regulates FLT3-ITD activity, and protein stability through deubiqutinase USP1, which we identify as a second dependency. Lastly, RSK1 inhibition utilizing a first-in-class RSK inhibitor, PMD-026, that is currently undergoing Phase 2 development for breast cancer, diminished leukemic disease burden in MV4-11 xenograft and syngeneic Flt3ITDTet2KO leukemia models. These findings illustrate an unconventional and promising therapeutic strategy targeting FLT3-ITD leukemia.

These findings suggest that MG132 exerts potent anti-leukemic effects through modulation of the Akt/FOXO3a/Bim axis, offering a promising therapeutic avenue for treating ALL.

USP5-dependentstabilization of HDAC1 contributed to cisplatin resistance and the malignancy of NSCLC by diminishing the levels of RILP acetylation, which suggested that targeting the HDAC1-USP5axis might represent a novel therapeutic strategy for overcoming DDP resistance in NSCLC patients.

Additionally, this degradation was inhibited by the proteasome inhibitor MG132. As a part of the ongoing effort to develop HIF-1 inhibitors, targeting the degradation of HIF-1α may offer an effective treatment strategy against solid tumors.

In PC cells, the inhibition of Rac1 leads to a time-dependent decline in YAP protein, which could be blocked by proteosome inhibitor MG132... These results reveal Rac1 as an oncogenic KRAS effector that contributes to YAP stabilization in PC cells. They also show that this regulation of YAP by Rac1 requires the SCFβTrCP ligase but occurs independently of the LATS1/2 kinases.

Polyubiquitinated bands of SOX17 were observed in MG132 treated OVTOKO, but not in OVISE or RMG-V OCCC cells...These findings indicate that SOX17 is not uniformly and heterogeneously expressed in OCCCs, independent of ARID1A deficiency. Impaired ubiquitin-mediated proteasome degradation may stabilize SOX17 in some OCCC cells.

The regulatory effect of FMRP on DDX5 protein expression was assessed using the protein synthesis inhibitor cycloheximide (CHX) and proteasome inhibitor MG132...On the other hand, the expression of these proteins was reversed by combined FMRP overexpression (P<0.05). FMRP targets DDX5 and promotes BC cell migration and EMT via the activation of the Wnt/β-catenin signaling pathway.

ESCC cell lines (KYSE150 and TE10) were treated with the proteasome inhibitor MG-132, followed by siRNA screening of deubiquitinases (DUBs) to identify regulators of WISP1...Furthermore, knockdown of USP13 or WISP1 impaired the activation of the Wnt/CTNNB1 signaling pathway and reduced immune checkpoint marker expression, indicating a mechanism by which USP13 promotes immune evasion in ESCC. USP13 stabilizes WISP1 through deubiquitination, enhancing ESCC progression by activating the Wnt/CTNNB1 pathway and promoting immune evasion, making USP13 a potential therapeutic target in ESCC.

HT exhibits anticancer activity against CRC probably by inhibiting Wnt/β-catenin signaling, with YAP playing an indispensible role during the process, highlighting HT as a potential novel candidate drug for CRC therapy.

Remarkably, chemical inactivation of NF-кB synergized MG132-induced cell mortality. All the findings suggest that NF-кB dictates aggresome assembly via upregulating HDAC6, and NF-кB inhibitor may serve as a potential drug potentiating proteasome inhibitor medicine-induced cytotoxicity during the treatment of cancer cells.

The mice were infected with lentivirus and treated with proteasome inhibitor MG132...Overexpression of IRF1 or silencing TREM2 reversed the improvement of TRIM21 overexpression on lung injury in mice. In conclusion, TRIM21 reduced IRF1 expression by ubiquitination to improve TREM2 expression and ameliorate sepsis-induced ALI.

MG132 enhances the therapeutic efficacy of cisplatin in human EC cells by suppressing the ubiquitin- proteasome pathway, reducing cell viability, enhancing apoptosis, and shifting the inflammatory response. These findings highlighted the potential of MG132 as an adjuvant in endometrial cancer chemotherapy. Further research is needed to explore detailed mechanisms and clinical applications of this combination therapy.

Meanwhile, the reduction of PD-L1 protein levels by Z2d/Z3d was counteracted by MG132, which indicated that Z2d/Z3d degraded PD-L1 through the proteasome pathway. Moreover, the molecular modeling results indicated that the HyT group of Z2d or Z3d extended the surface of the protein to mimic the misfold. Importantly, our work also identified a novel HyT, which could be applied to develop the HyTTD for other target proteins.

Treatment of Kindlin-2-deficient cells with the proteasome inhibitor MG-132 restored the expression of both β1-Integrin and TβRI...This study identifies a novel function of Kindlin-2 in stabilizing the β1-Integrin:TβRI complexes and regulating their downstream oncogenic signaling. The translational implications of these findings are substantial, potentially unveiling new therapeutically targeted pathways crucial for the treatment of TNBC tumors.

Our results show that CAY10598 decreases the levels of client proteins of Hsp90 in HCT116 cells, an effect reversible by pretreatment with the ROS scavenger N-acetyl cysteine (NAC) or the proteasome inhibitor MG132, indicating that the degradation is likely driven by ROS...Additionally, CAY10598 suppressed the growth of HCT116 cells implanted in mice. Our findings reveal that CAY10598 induces apoptosis in cancer cells by a novel mechanism involving the ROS-dependent cleavage of Hsp90, thereby inhibiting the function of crucial Hsp90 client proteins.

By employing cycloheximide (CHX), MG132, and chloroquine (CQ), we investigated whether NaB affects HIF-1α protein levels via the autophagy pathway. Furthermore, a human colorectal cancer xenograft model confirmed that butyric acid inhibited tumor growth in vivo, correlating with SIRT4 and HIF-1α modulation. In conclusion, our findings indicate that NaB hinders colorectal cancer progression by disrupting aerobic glycolysis mediated by SIRT4/HIF-1α.

This inhibitory effect on HIF-1α was corroborated by experiments utilizing the protease inhibitor MG-132 and protein synthesis inhibitor CHX, indicating that compound M2 diminishes HIF-1α levels by reducing its synthesis...In vivo studies demonstrated that compound M2 exhibited low toxicity and effectively curbed tumor growth. Immunohistochemistry analyses validated that compound M2 effectively suppressed the expression of HIF-1α and VEGF in tumor tissues, underscoring its potential as a promising therapeutic agent for targeting tumor angiogenesis.

IκBα protein expression level was further analyzed by Western blot after being treated with cycloheximide (CHX) and MG132...Conclusion Overexpression of TTC36 inhibits the inflammatory response of HK2 cells, reduces cell apoptosis, promotes proliferation, and strengthens tight junctions. The mechanism may be to inhibit the activation of NF-κB signaling pathway by enhancing the expression of IκBα, thereby reducing the cell damage caused by inflammatory response.

Moreover, goose primary hepatocytes were co-treated with glucose, harringtonine and carbobenzoxy-L-leucyl-L-leucyl-L-leucinal (MG132)...In summary, glucose may inhibit the inflammatory response in goose fatty liver by increasing the ubiquitination level of PKA. Additionally, RNF135 and KCMF1 may be involved in the regulation of PKA ubiquitination level as E3 ubiquitination ligases.

Here, we used an integrated drug repositioning approach based on transcriptomics data and structure-based virtual screening to identify compounds with gene signatures similar to three known proteasome inhibitors (PIs; bortezomib, MG-132, and MLN-2238)...Using this approach, we identified six compounds with PI properties ((-)-kinetin-riboside, manumycin-A, puromycin dihydrochloride, resistomycin, tegaserod maleate, and thapsigargin)...As shown with bortezomib, only manumycin-A, puromycin dihydrochloride, and tegaserod maleate resulted in excessive accumulation of ubiquitinated proteins and elevated HMOX1 expression. Taken together, our integrated drug repositioning approach and subsequent in vitro validation studies identified six compounds demonstrating properties similar to proteasome inhibitors.

This study shows that the application of similar or diverse assay protocols allows to detect various influences on HIF heterodimerization as a key signaling event in the oxygen sensing pathway: increased HIF heterodimerization (roxadustat, MG-132), decreased HIF heterodimerization (PX-478, ibuprofen) and direct (HIF isoform-selective) heterodimerization inhibiting effects (PT-2385). Specific and general considerations include cell-based, technical and disease/drug-related aspects (e.g., non-specific effects, color interference). In summary, the versatility of these bioassays offers benefits in widespread applications regarding drug discovery and pharmacological characterization of various therapeutics, applying either the same or optimized experimental protocols.

Silencing TMOD1 also inhibited tumor growth by elevating KPNA2-mediated autophagy in nude mice bearing MOLM-13 xenografts. Collectively, our data demonstrated that TMOD1 could be a novel therapeutic target for AML treatment.

In L6 myotubes treated with PYR-41, chloroquine increased the abundance of the epidermal growth factor receptor, but did not prevent the suppression of PDK1. Collectively, our results suggest that cultured myotubes degrade PDK1 via a pathway that cannot be inhibited by MG132, PYR-41, and/or chloroquine.

Our analysis shows that XPO5 expression is a reliable prognostic indicator for patients with HCC and is significantly associated with immune cell infiltration.

Furthermore, c-Myc degradation by CPSF6 depletion was disturbed by FBW7 depletion or treatment with the proteasomal inhibitor MG132. Consistently, immunohistochemistry showed that CPSF6 depletion reduced the growth of Hep3B cells in BALB/c mice in orthotopic and xenograft tumor models by inhibiting tumor microenvironment-associated proteins. Overall, these findings suggest that CPSF6 enhances the Warburg effect for immune escape and angiogenesis, leading to cancer progression via c-Myc, mediated by the HK, PD-L1, and VEGF networks, with synergistic potential with sorafenib as a molecular target for liver cancer therapy.