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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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			Action	DRS
	20230206_LU_LC2_BSP_N2_NOA_LG90.mgf	Mgf
	20230206_LU_LC2_BSP_N2_NOA_LG90.raw	Raw
	20230206_LU_LC2_BSP_N3_NOA_LG90.mgf	Mgf
	20230206_LU_LC2_BSP_N3_NOA_LG90.raw	Raw
	20230206_LU_LC2_BSP_N4_NOA_LG90.mgf	Mgf

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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.

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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.

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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.

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Proteasome degradation of synthetic ubiquitinated globin

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

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Energetics- and transport-related protein abundance responds differentially to salt in Oryza australiensis roots

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