Dataset Information

Arachidonic acid suppresses natural killer cell functions by interfering with multiple signal transduction pathways

ABSTRACT: High levels of the polyunsaturated fatty acid arachidonic acid (AA) in the ovarian carcinoma (OC) microenvironment are associated with short relapse-free survival. OC progression is also linked to impaired immunosurveillance, due in part to dysfunctional natural killer (NK) cells. In the present study, we have combined phosphoproteomics, transcriptional profiling and functional assays to study the impact of AA on NK cell functions. Our data show that AA (i) impairs interleukin-2-mediated NK cell proliferation and pro-inflammatory gene expression by blocking STAT1-dependent signaling, (ii) interferes with NK cell receptor (NCR) signaling, including inhibition of MICA-induced ERK phosphorylation and (iii) affects the production of reactive oxygen species. Intriguingly, low expression of several NK cell receptors is associated with a short survival of OC patients, suggesting that AA, dysfunction of NK cells and OC progression are functionally linked. - Orbitrap 480 - TMT labelling - FeNTA phospho-enrichment - DDA

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Prof. Dr. Rolf Mueller

PROVIDER: MSV000094127 | MassIVE | Tue Feb 20 06:17:00 GMT 2024

SECONDARY ACCESSION(S): PXD049958

REPOSITORIES: MassIVE

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Arachidonic acid impairs natural killer cell functions by disrupting signaling pathways driven by activating receptors and reactive oxygen species.

Hammoud Mohamad K MK Meena Celina C Dietze Raimund R Hoffmann Nathalie N Szymanski Witold W Finkernagel Florian F Nist Andrea A Stiewe Thorsten T Graumann Johannes J von Strandmann Elke Pogge EP Müller Rolf R

Cell communication and signaling : CCS 20241119 1

<h4>Background</h4>High levels of the polyunsaturated fatty acid arachidonic acid (AA) within the ovarian carcinoma (OC) microenvironment correlate with reduced relapse-free survival. Furthermore, OC progression is tied to compromised immunosurveillance, partially attributed to the impairment of natural killer (NK) cells. However, potential connections between AA and NK cell dysfunction in OC have not been studied.<h4>Methods</h4>We employed a combination of phosphoproteomics, transcriptional pr ...[more]

PMID: 39563446

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Project description:Arachidonic acid (AA) is a polyunsaturated fatty acid present at high concentrations in the ovarian cancer (OC) microenvironment and is associated with poor clinical outcome. In the present study, we elucidate a potential link between AA and pro-tumorigenic macrophage polarization. Methods: AA-triggered signal transduction was studied in primary monocyte-derived macrophages (MDMs) by phosphoproteomics, transcriptional profiling, measurement of intracellular Ca2+ accumulation and reactive oxygen species production in conjunction with bioinformatic analyses. Functional effects were investigated by actin filament staining, quantification of macropinocytosis and analysis of extracellular vesicle release. Results: We identified the ASK1 - p38 (MAPK13/14) axis as a central constituent of signal transduction pathways triggered by non-metabolized AA. This pathway was induced by the Ca2+-triggered activation of calmodulin kinase II, and to a minor extent by ROS generation in a subset of donors. Activated p38 in turn was linked to a transcriptional stress response associated with a poor relapse-free survival. Consistent with the phosphorylation of the p38 substrate HSP27 and the (de)phosphorylation of multiple regulators of Rho family GTPases, AA impaired actin filament organization and inhibited actin-driven macropinocytosis. AA also affected the phosphorylation of proteins regulating vesicle biogenesis, and consistently, AA enhanced the release of tetraspanin-containing exosomes. Finally, we identified phospholipase A2 Group 2A (PLA2G2A) as the clinically most relevant enzyme producing extracellular AA, providing further potentially theranostic options. Conclusion: Our results suggest that AA contributes to an unfavorable clinical outcome of OC by promoting the pro-tumorigenic phenotype of tumor-associated macrophages. Besides critical AA-regulated signal transduction proteins identified in the present study, PLA2G2A might represent a potential prognostic tool and therapeutic target to interfere with OC progression.