Phosphoproteomics identify arachidonic-acid-regulated signal transduction pathways modulating macrophage functions with implications for ovarian cancer
| Autor: | María Gómez-Serrano, Andrea Nist, Silke Reinartz, Annika Unger, Tim Bieringer, Raimund Dietze, Viviane Ponath, Sabine Müller-Brüsselbach, Elke Pogge von Strandmann, Mohamad K Hammoud, Christian Preußer, Johannes Graumann, Thorsten Stiewe, Anna M. Sokol, Florian Finkernagel, Rolf Müller |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Transcription Genetic macropinocytosis Actin filament organization Medicine (miscellaneous) Group II Phospholipases A2 Extracellular Vesicles 03 medical and health sciences 0302 clinical medicine Phospholipase A2 Hsp27 Ca2+/calmodulin-dependent protein kinase Tumor Microenvironment arachidonic acid Humans Phosphorylation Pharmacology Toxicology and Pharmaceutics (miscellaneous) Ovarian Neoplasms biology Chemistry Macrophages Phosphoproteomics phosphoproteomics Extracellular vesicle Cell biology ovarian cancer 030104 developmental biology 030220 oncology & carcinogenesis biology.protein Calcium Female Neoplasm Recurrence Local Signal transduction Reactive Oxygen Species Signal Transduction Research Paper |
| Zdroj: | Theranostics |
| ISSN: | 1838-7640 |
| DOI: | 10.7150/thno.52442 |
| Popis: | Arachidonic acid (AA) is a polyunsaturated fatty acid present at high concentrations in the ovarian cancer (OC) microenvironment and associated with a poor clinical outcome. In the present study, we have unraveled a potential link between AA and macrophage functions. 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 - p38δ/α (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 exosome-like vesicles. 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 impacting the 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. |
| Databáze: | OpenAIRE |
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