Arachidonic acid impairs natural killer cell functions by disrupting signaling pathways driven by activating receptors and reactive oxygen species
Abstract Background 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 na...
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BMC
2024-11-01
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| Series: | Cell Communication and Signaling |
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| Online Access: | https://doi.org/10.1186/s12964-024-01940-z |
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| author | Mohamad K. Hammoud Celina Meena Raimund Dietze Nathalie Hoffmann Witold Szymanski Florian Finkernagel Andrea Nist Thorsten Stiewe Johannes Graumann Elke Pogge von Strandmann Rolf Müller |
| author_facet | Mohamad K. Hammoud Celina Meena Raimund Dietze Nathalie Hoffmann Witold Szymanski Florian Finkernagel Andrea Nist Thorsten Stiewe Johannes Graumann Elke Pogge von Strandmann Rolf Müller |
| author_sort | Mohamad K. Hammoud |
| collection | DOAJ |
| description | Abstract Background 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. Methods We employed a combination of phosphoproteomics, transcriptional profiling and biological assays to investigate AA’s impact on NK cell functions. Results AA (i) disrupts interleukin-2/15-mediated expression of pro-inflammatory genes by inhibiting STAT1-dependent signaling, (ii) hampers signaling by cytotoxicity receptors through disruption of their surface expression, (iii) diminishes phosphorylation of NKG2D-induced protein kinases, including ERK1/2, LYN, MSK1/2 and STAT1, and (iv) alters reactive oxygen species production by transcriptionally upregulating detoxification. These modifications lead to a cessation of NK cell proliferation and a reduction in cytotoxicity. Conclusion Our findings highlight significant AA-induced alterations in the signaling network that regulates NK cell activity. As low expression of several NK cell receptors correlates with shorter OC patient survival, these findings suggest a functional linkage between AA, NK cell dysfunction and OC progression. |
| format | Article |
| id | doaj-art-b5b59f79e7714241a2f9d27ed2f57ac0 |
| institution | OA Journals |
| issn | 1478-811X |
| language | English |
| publishDate | 2024-11-01 |
| publisher | BMC |
| record_format | Article |
| series | Cell Communication and Signaling |
| spelling | doaj-art-b5b59f79e7714241a2f9d27ed2f57ac02025-08-20T02:33:31ZengBMCCell Communication and Signaling1478-811X2024-11-0122112310.1186/s12964-024-01940-zArachidonic acid impairs natural killer cell functions by disrupting signaling pathways driven by activating receptors and reactive oxygen speciesMohamad K. Hammoud0Celina Meena1Raimund Dietze2Nathalie Hoffmann3Witold Szymanski4Florian Finkernagel5Andrea Nist6Thorsten Stiewe7Johannes Graumann8Elke Pogge von Strandmann9Rolf Müller10Department of Translational Oncology, Center for Tumor Biology and Immunology, Philipps UniversityInstitute of Tumor Immunology, Center for Tumor Biology and Immunology, Philipps UniversityDepartment of Translational Oncology, Center for Tumor Biology and Immunology, Philipps UniversityInstitute of Tumor Immunology, Center for Tumor Biology and Immunology, Philipps UniversityInstitute of Translational Proteomics, Biochemical/Pharmacological Centre, Philipps UniversityDepartment of Translational Oncology, Center for Tumor Biology and Immunology, Philipps UniversityGenomics Core Facility, Philipps UniversityGenomics Core Facility, Philipps UniversityInstitute of Translational Proteomics, Biochemical/Pharmacological Centre, Philipps UniversityInstitute of Tumor Immunology, Center for Tumor Biology and Immunology, Philipps UniversityDepartment of Translational Oncology, Center for Tumor Biology and Immunology, Philipps UniversityAbstract Background 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. Methods We employed a combination of phosphoproteomics, transcriptional profiling and biological assays to investigate AA’s impact on NK cell functions. Results AA (i) disrupts interleukin-2/15-mediated expression of pro-inflammatory genes by inhibiting STAT1-dependent signaling, (ii) hampers signaling by cytotoxicity receptors through disruption of their surface expression, (iii) diminishes phosphorylation of NKG2D-induced protein kinases, including ERK1/2, LYN, MSK1/2 and STAT1, and (iv) alters reactive oxygen species production by transcriptionally upregulating detoxification. These modifications lead to a cessation of NK cell proliferation and a reduction in cytotoxicity. Conclusion Our findings highlight significant AA-induced alterations in the signaling network that regulates NK cell activity. As low expression of several NK cell receptors correlates with shorter OC patient survival, these findings suggest a functional linkage between AA, NK cell dysfunction and OC progression.https://doi.org/10.1186/s12964-024-01940-zArachidonic acidCytotoxicity receptorsInterleukin 2Natural killer (NK) cellsNKG2DOvarian carcinoma |
| spellingShingle | Mohamad K. Hammoud Celina Meena Raimund Dietze Nathalie Hoffmann Witold Szymanski Florian Finkernagel Andrea Nist Thorsten Stiewe Johannes Graumann Elke Pogge von Strandmann Rolf Müller Arachidonic acid impairs natural killer cell functions by disrupting signaling pathways driven by activating receptors and reactive oxygen species Cell Communication and Signaling Arachidonic acid Cytotoxicity receptors Interleukin 2 Natural killer (NK) cells NKG2D Ovarian carcinoma |
| title | Arachidonic acid impairs natural killer cell functions by disrupting signaling pathways driven by activating receptors and reactive oxygen species |
| title_full | Arachidonic acid impairs natural killer cell functions by disrupting signaling pathways driven by activating receptors and reactive oxygen species |
| title_fullStr | Arachidonic acid impairs natural killer cell functions by disrupting signaling pathways driven by activating receptors and reactive oxygen species |
| title_full_unstemmed | Arachidonic acid impairs natural killer cell functions by disrupting signaling pathways driven by activating receptors and reactive oxygen species |
| title_short | Arachidonic acid impairs natural killer cell functions by disrupting signaling pathways driven by activating receptors and reactive oxygen species |
| title_sort | arachidonic acid impairs natural killer cell functions by disrupting signaling pathways driven by activating receptors and reactive oxygen species |
| topic | Arachidonic acid Cytotoxicity receptors Interleukin 2 Natural killer (NK) cells NKG2D Ovarian carcinoma |
| url | https://doi.org/10.1186/s12964-024-01940-z |
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