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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): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Christian Münch

LAB HEAD: Christian Münch

PROVIDER: PXD035951 | Pride | 2024-03-26

REPOSITORIES: Pride

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			Action	DRS
	20220317_MAA_PP_26S_9_NOA.mgf	Mgf
	20220317_MAA_PP_26S_9_NOA.mzid.gz	Mzid
	20220317_MAA_PP_26S_9_NOA.raw	Raw
	20220317_MAA_PP_26S_OA.mgf	Mgf
	20220317_MAA_PP_26S_OA.mzid.gz	Mzid

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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 | PXD041458 | 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

Targeting the MAtrix REgulating MOtif, MAREMO, abolishes hallmarks of cancer

Project description:Tumor targeted therapies have been largely inefficient due to lack of concomitant effects on the tumor microenvironment (TME). We investigated the MAtrix REgulating MOtif (MAREMO) mimicking peptide MP5, that inhibits the pro-tumorigenic extracellular matrix (ECM) molecule tenascin-C, using immunocompetent autologous breast cancer bearing mice. MP5 treatment led to tumor regression and reduced tumor cell dissemination. Several cancer hallmarks were abolished such as tumor cell promoting growth suppression and inhibition of plasticity enhancing responsiveness to death inducers. MP5 acts on other TME players leading to blood vessel normalization and depletion of fibroblasts diminishing the ECM as an orchestrator of immune suppression, causing immune cell infiltration and reactivation of anti-tumor immunity involving IFNgamma. Thus, targeting the tumor matrix using MAREMO in tenascin-C represents a powerful novel anti-cancer strategy.

2024-01-20 | E-MTAB-13677 | biostudies-arrayexpress

Tumor-derived retinoic acid regulates intratumoral monocyte differentiation to promote immune suppression and resistance to immune checkpoint blockade

Project description:The immunosuppressive tumor microenvironment (TME) is a major barrier to immunotherapy. Within solid tumors, why monocytes preferentially differentiate into immunosuppressive tumor associated macrophages (TAMs) but not immunostimulatory dendritic cells (DCs) remains unclear. Using multiple murine sarcoma models, we found that the TME induced retinoic acid (RA) production by tumor cells, which polarized intratumoral monocyte differentiation towards TAMs and away from DCs via suppression of DC-promoting transcription factor Irf4. Genetic inhibition of RA production by tumor cells or pharmacologic inhibition of RA signaling within TME increased stimulatory monocyte-derived cells, enhanced T cell-dependent anti-tumor immunity and demonstrated striking synergy with immune checkpoint blockade. Further, RA responsive gene signature in human monocytes correlated with an immunosuppressive TME in multiple human tumors. RA has been long considered as an anti-cancer agent, but our work demonstrates its tumorigenic capability via myeloid-mediated immune suppression and provides proof of concept for targeting this pathway for tumor immunotherapy.

2020-04-01 | GSE144507 | GEO

Gene expression in sarcoma cell lines

Project description:As a high-grade soft-tissue sarcoma (STS), undifferentiated pleomorphic sarcoma (UPS) is highly recurrent and malignant. UPS is categorized as “tumor of uncertain differentiation” and few options for treatment resulting from lack of targetable genetic alterations. There are also few cell lines representative subtype for UPS, leading to poor experimental evidence. Here, we have established and characterized new cell lines derived from recurrent two UPS tissues. Cells were obtained UPS tissues by mincing followed by extracting or dissociating using enzymes and cultured by regular culture environment. Cells were maintained and immortal for months without artificial treatment and some cell clones were tumorigenic in immunodeficient mouse model. Interestingly, some cells formed tumor in vivo when injected after aggregation in non-adherent culture system for 24 h. The tissues from in vivo study and tissues from patients were compared if it is representative for UPS by immunohistochemistry. Pathways related to cell cycle as DNA replication were common between cell clones while cell clones, tumorigenic in regardless of aggregation for injection, were increased expression of pathways related to cell-cell adhesion, as well as cell-cell signaling, implying a role of mesenchymal to epithelial transition for tumorigenicity in vivo. This study showed that new UPS cell lines might be a good resource for UPS study to get new insights leading to better therapeutic strategy against UPS.

2023-12-31 | GSE213936 | GEO

Expression data from cultured mouse bone-marrow monocytes.

Project description:Retinoic acid signaling regulates monocyte differentiation into dendritic cells or macrophages. We used microarrays to uncover gene expression changes associated with retinoic acid exposure in mouse monocytes. The immunosuppressive tumor microenvironment (TME) is a major barrier to immunotherapy. Within solid tumors, why monocytes preferentially differentiate into immunosuppressive tumor associated macrophages (TAMs) but not immunostimulatory dendritic cells (DCs) remains unclear. Using multiple murine sarcoma models, we found that the TME induced retinoic acid (RA) production by tumor cells, which polarized intratumoral monocyte differentiation towards TAMs and away from DCs via suppression of DC-promoting transcription factor Irf4. Genetic inhibition of RA production by tumor cells or pharmacologic inhibition of RA signaling within TME increased stimulatory monocyte-derived cells, enhanced T cell-dependent anti-tumor immunity and demonstrated striking synergy with immune checkpoint blockade. Further, RA responsive gene signature in human monocytes correlated with an immunosuppressive TME in multiple human tumors. RA has been long considered as an anti-cancer agent, but our work demonstrates its tumorigenic capability via myeloid-mediated immune suppression and provides proof of concept for targeting this pathway for tumor immunotherapy.

2020-05-01 | GSE144609 | GEO

Expression data from cultured human monocytes

Project description:Retinoic acid signaling regulates monocyte differentiation into dendritic cells or macrophages. We used microarrays to uncover gene expression changes associated with retinoic acid exposure in human monocytes. The immunosuppressive tumor microenvironment (TME) is a major barrier to immunotherapy. Within solid tumors, why monocytes preferentially differentiate into immunosuppressive tumor associated macrophages (TAMs) but not immunostimulatory dendritic cells (DCs) remains unclear. Using multiple murine sarcoma models, we found that the TME induced retinoic acid (RA) production by tumor cells, which polarized intratumoral monocyte differentiation towards TAMs and away from DCs via suppression of DC-promoting transcription factor Irf4. Genetic inhibition of RA production by tumor cells or pharmacologic inhibition of RA signaling within TME increased stimulatory monocyte-derived cells, enhanced T cell-dependent anti-tumor immunity and demonstrated striking synergy with immune checkpoint blockade. Further, RA responsive gene signature in human monocytes correlated with an immunosuppressive TME in multiple human tumors. RA has been long considered as an anti-cancer agent, but our work demonstrates its tumorigenic capability via myeloid-mediated immune suppression and provides proof of concept for targeting this pathway for tumor immunotherapy.

2020-05-01 | GSE144608 | GEO

Expression data from tumor-infiltrating macrophages.

Project description:The microenvironment has profound effect on macrophage phenotype. Here we examine the phenotype of macrophages infiltrating murine undifferentiated pleomorphic sarcomas. We used microarray to examine gene expression profile of tumor-associated macrophages in murine undifferentiated pleomorphic sarcomas. The immunosuppressive tumor microenvironment (TME) is a major barrier to immunotherapy. Within solid tumors, why monocytes preferentially differentiate into immunosuppressive tumor associated macrophages (TAMs) but not immunostimulatory dendritic cells (DCs) remains unclear. Using multiple murine sarcoma models, we found that the TME induced retinoic acid (RA) production by tumor cells, which polarized intratumoral monocyte differentiation towards TAMs and away from DCs via suppression of DC-promoting transcription factor Irf4. Genetic inhibition of RA production by tumor cells or pharmacologic inhibition of RA signaling within TME increased stimulatory monocyte-derived cells, enhanced T cell-dependent anti-tumor immunity and demonstrated striking synergy with immune checkpoint blockade. Further, RA responsive gene signature in human monocytes correlated with an immunosuppressive TME in multiple human tumors. RA has been long considered as an anti-cancer agent, but our work demonstrates its tumorigenic capability via myeloid-mediated immune suppression and provides proof of concept for targeting this pathway for tumor immunotherapy.

2020-05-01 | GSE144611 | GEO

Transcription profiling of human cell cancer line treated with bortezomib or Eeyarestatin I (EerI) reveals ERAD inhibitors integrate ER stress with an epigenetic mechanism to activate BH3 only protein NOXA in cancer cells

Project description:The ubiquitin-proteasome system (UPS) has recently emerged as a major target for drug development in cancer therapy. The proteasome inhibitor bortezomib has clinical activity in multiple myeloma and mantle cell lymphoma. Here we report that Eeyarestatin I (EerI), a chemical inhibitor that blocks ER-associated protein degradation (ERAD), has anti-tumor and biologic activities similar to bortezomib, and can synergize with bortezomib. Like bortezomib, EerI-induced cytotoxicity requires the upregulation of the BH3 only pro-apoptotic protein NOXA. We further demonstrate that both EerI and bortezomib activate NOXA via an unanticipated mechanism that requires cooperation between two processes: First, these agents elicit an integrated stress response program at the ER to activate the CREB/ATF transcription factors ATF3 and ATF4. We show that ATF3 and ATF4 form a complex capable of binding to the NOXA promoter, which is required for NOXA activation. Second, EerI and bortezomib also block ubiquitination of histone H2A to relieve its inhibition on NOXA transcription. Our results identify a class of anti-cancer agents that integrate ER stress response with an epigenetic mechanism to induce cell death. Experiment Overall Design: 1. EerI 10 vs 0 Experiment Overall Design: 2. EerI 10 vs 0 Experiment Overall Design: 3. Bzm 10 vs 0 Experiment Overall Design: 4. Bzm 10 vs 0

2009-02-28 | E-GEOD-14003 | biostudies-arrayexpress

Expression data from human HeLa cells exposed to interferon gamma for 2, 4, and 6 hours

Project description:The ubiquitin proteasome system (UPS) is known to possess important regulatory functions in the immune response. To gain a better and first comprehensive insight into the mechanisms of remodelling of UPS related gene expression inresponse to interferon-gamma, we undertook a comparative gene expression profiling during interferon-gamma stimulation at very early time points. Keywords: time course

2010-05-11 | GSE21760 | GEO

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