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Endogenous anti-tumorigenic nitro-fatty acids are a novel type of direct and potent inhibitor of the 26S proteasome

ABSTRACT: Nitro-fatty acids (NFAs) are endogenous lipid mediators causing a broad spectrum of anti-inflammatory effects by covalent modification of key proteins within inflammatory signaling pathways. Their potential as anti-tumorigenic therapeutics has recently been demonstrated in animal models of solid tumors. Herein, we evaluated the anti-tumorigenic effects of NFAs in colon carcinoma cells and other solid and leukemic tumor cell lines. NFAs inhibited the ubiquitin–proteasome system (UPS) by directly targeting the 26S proteasome, leading to polyubiquitination and inhibition of the proteasomal activities. Suppression of the UPS induced the unfolded protein response, resulting in tumor cell death. The NFA-mediated effects were rather strong, highly specific, largely irreversible, and represent a mechanistically new mode of action for UPS suppression. The present study extends the knowledge on the biological actions of NFAs as possible endogenous tumor-suppressive factors. Furthermore, NFAs might be lead structures for the design of a novel class of direct proteasome inhibitors.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Colon

SUBMITTER: Christian Münch

LAB HEAD: Dr. Christian Münch

PROVIDER: PXD041458 | Pride | 2024-03-26

REPOSITORIES: Pride

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Endogenous anti-tumorigenic nitro-fatty acids are a novel type of direct and potent inhibitor of the 26S proteasome

Project description:Nitro-fatty acids (NFAs) are endogenous lipid mediators causing a broad spectrum of anti-inflammatory effects by covalent modification of key proteins within inflammatory signaling pathways. Their potential as anti-tumorigenic therapeutics has recently been demonstrated in animal models of solid tumors. Herein, we evaluated the anti-tumorigenic effects of NFAs in colon carcinoma cells and other solid and leukemic tumor cell lines. NFAs inhibited the ubiquitin–proteasome system (UPS) by directly targeting the 26S proteasome, leading to polyubiquitination and inhibition of the proteasomal activities. Suppression of the UPS induced the unfolded protein response, resulting in tumor cell death. The NFA-mediated effects were rather strong, highly specific, largely irreversible, and represent a mechanistically new mode of action for UPS suppression. The present study extends the knowledge on the biological actions of NFAs as possible endogenous tumor-suppressive factors. Furthermore, NFAs might be lead structures for the design of a novel class of direct proteasome inhibitors.

2024-03-26 | PXD035951 | Pride

26S proteasome is conserved, therapeutically relevant mediator of mutant p53 gain-of-function in cancer

Project description:Mutant p53 proteins, resulting form frequent TP53 tumor suppressor missense mutations, possess gain-of-function activities and are among the most widespread and robust oncoproteins in human tumors. They are potentially important but understudied therapeutic targets. No studies to date have distinguished common, therapeutically relevant mutant p53 gain-of-function effects, from effects specific to different mutant variants and cell backgrounds. Here we identify 26S proteasome machinery as the common downstream effector controlled by mutant p53s in Triple Negative Breast Cancer (TNBC - aggressive carcinomas with TP53 as the most frequently mutated locus) and conserved in other human cancers. We have identified this pathway using a combination of single-model, multi-method vertical analysis (whole cell proteome, RNA sequencing an ChIP sequencing) and multi-cell line, horizontal analysis of transcriptiomes. We found that different missense mutant p53s regardless of the cell background transcriptionaly activate whole 26S proteasome machinery. Proteasome activity is significantly increased in p53 mutant versus wild-type or knockdown/null status - in cellular and mouse models as well as in human breast tumors. Increased proteasome activity leads to inhibition of tumor suppressive pathways. The control of mutant p53 over proteasome transcription and activity results in the increased resistance to proteasome inhibitors. By combining the mutant p53 targeting agents and proteasome inhibitor we were able to overcome the “bounce-back” proteasome inhibitor resistance mechanism in mutant p53 bearing TNBC cells and xenografts in vivo.

2016-05-03 | PXD001673 | Pride

Endogenous anti-tumorigenic nitro-fatty acids potently suppress the ubiquitin-proteasome system

Project description:Nitro-fatty acids (NFAs) are endogenously formed lipid mediators that cause a broad spectrum of anti-inflammatory effects by covalent modification of key proteins within inflammatory signaling pathways. Their potential as therapeutics has been demonstrated in numerous animal models of disease. Herein, we evaluated the anti-tumorigenic effects of NFAs in the colon carcinoma cell line Caco-2 and other solid and leukemic tumor cell lines. NFAs inhibited the ubiquitin–proteasome system (UPS), leading to polyubiquitination and inhibition of the proteasome activities. Suppression of the UPS induced the pro-apoptotic transcription factor CHOP by activation of the unfolded protein response (UPR), resulting in tumor cell death. NFA-mediated effects on UPS and UPR were rather strong, highly specific, largely irreversible, and represent a mechanistically new mode of action for pharmacological suppression of the UPS. Taking into account their favorable safety profile in clinical phase I trials in combination with their well-recognized anti-tumorigenic efficacy covering solid tumors, we conclude that NFAs are innovative proteasome inhibitor drug candidates that may have a large potential to overcome the limitations of the classical proteasome inhibitors.

2024-03-26 | PXD023372 | Pride

PTMs in yeast complexes - We investigate the roles of natively present PTMs on stability of interactions in three large and essential yeast Saccharomyces cerevisiae complexes: exosome, RNA polymerase II and 26S proteasome.

Project description:We investigate the roles of natively present PTMs on stability of interactions in three large and essential yeast Saccharomyces cerevisiae complexes: exosome, RNA polymerase II and 26S proteasome.

2018-09-13 | PXD008324 | Pride

Proteasome degradation of synthetic ubiquitinated globin

Project description:Analysis of the peptides resulting from proteasome-mediated degradation of K48-linked tetra ubiquitin conjugated to alpha globin

2021-08-24 | PXD004456 | Pride

Ubiquitin remenants identification following in vitro assay of 20S and 26S proteasome using naked and ubiquitined cyclin

Project description:A systematic and comparative study of the proteolysis products generated by purified human 26S and 20S proteasome following the in vitro cleavage of non-modified (naked), mono-ubiquitinated and poly-ubiquitinated cyclin B.

2021-11-02 | PXD028912 | Pride

Arabidopsis cell LC-MSMS - Proteomics analysis reveals a highly heterogeneous proteasome composition and the post-translational regulation of peptidase activity under pathogen signaling in plants

Project description:26S proteasome was affinity-purified with anti-FLAG beads and separated by 2-DE method. Each spot was cut and digested by Trypsin enzyme, which finaly applied for LC-MS/MS nalysis using a LTQ-Orbitrap XL (Thermo Scientific). The obtained spectra were compared against 35,386 sequences in The Arabidopsis Information Resource 10 (TAIR10; http://www.arabidopsis.org/) using the MASCOT server (version 2.4; Matrix Science) with the following search parameters: threshold set-off at 0.05 in the ion-score cut-off; protein identification cut-off set to two assigned spectra per predicted protein; peptide tolerance at 10 ppm; MS/MS tolerance at +/- 0.5 Da; peptide charge of 2+ or 3+; trypsin as the enzyme and allowing up to one missed cleavage; carboxymethylation on cysteines as a fixed modification and oxidation on methionine as a variable modification.

2014-07-28 | PXD000417 | Pride

Enabling Photoactivated Cross-linking Mass Spectrometric Analysis of Protein Complexes by Novel MS-cleavable Cross-linkers

Project description:Cross-linking mass spectrometry (XL-MS) is a powerful tool for studying protein-protein interactions and elucidating architectures of protein complexes. While residue-specific XL-MS studies have been very successful, accessibility of interaction regions non-targetable by specific chemistries remain difficult. Photochemistry has shown great potential in capturing those regions due to nonspecific reactivity, but low yields and high complexities of photocross-linked products have hindered their identification, limiting current studies predominantly to single proteins. Here, we describe the development of three novel MS-cleavable heterobifunctional cross-linkers, namely SDASO (Succinimidyl diazirine sulfoxide), to enable fast and accurate identification of photocross-linked peptides by MSn. The MSn-based workflow allowed SDASO XL-MS analysis of the yeast 26S proteasome, demonstrating the feasibility of photocross-linking of large protein complexes for the first time. Comparative analyses have revealed that SDASO cross-linking is robust and captures interactions complementary to residue-specific reagents, providing the foundation for future applications of photocross-linking in complex XL-MS studies.

2021-05-07 | PXD022690 | Pride

Myelin basic protein fragmentation by engineered human proteasomes with different catalytic phenotypes revealed direct peptide ligands of MS-associated and protective HLA class I molecules

Project description:Proteasomes exist in mammalian cells in multiple combinatorial variants due to the broadly diversified regulatory particles and catalytic subunits exchange. Here, using biotin carboxyl carrier domain of transcarboxylase from Propionibacterium shermanii fused with different proteasome subunits of catalytic and regulatory particles, we report comprehensive characterization of highly homogenous one-step purified human constitutive and immune 20S and 26S/30S proteasomes. Hydrolysis of multiple sclerosis (MS) autoantigen, myelin basic protein (MBP), by engineered human proteasomes with different catalytic phenotypes revealed peptides, which may be directly loaded on the HLA class I. Prediction of affinity of HLA class I to these peptides demonstrated that protective HLA I alleles are high affinity binders, whereas MS-associated alleles tend to have moderate-to-low affinity. Core peptide QDENPVVHFF, originated from the encephalitogenic MBP part, and its deaminated form was shown to be high affinity ligand for the protective HLA A*44, -B*40 and -B*35 alleles, demonstrating complexity of the autoimmune neurodegeneration.

2023-01-13 | PXD038387 | Pride

26S proteasome crosslinking mass spectrometry data for mi-filter

Project description:In this project we are describing a novel mono- and intralink filter (mi-filter) that is applicable to any kind of crosslinking data and workflow. It stipulates that only proteins for which at least one monolink or intra-protein crosslink has been identified within a given dataset are considered for an inter-protein cross-link and therefore participate in a PPI. We show that this simple and intuitive filter has a dramatic effect on all types of crosslinking-data ranging from single protein complexes, over medium-complexity affinity enrichments to proteome-wide settings and significantly improves false-discovery rates for inter-protein links in all types of XL-MS data.

2022-12-14 | PXD031215 | Pride

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