Communication between human macrophages and epithelial cancer cell lines dictates lipid mediator biosynthesis
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Cellular and Molecular Life Sciences
ORIGINAL ARTICLE
Communication between human macrophages and epithelial cancer cell lines dictates lipid mediator biosynthesis Markus Werner1 · Simona Pace1 · Anna Czapka1 · Paul M. Jordan1 · Jana Gerstmeier1 · Andreas Koeberle1,2 · Oliver Werz1 Received: 9 August 2019 / Revised: 1 November 2019 / Accepted: 4 December 2019 © Springer Nature Switzerland AG 2020
Abstract In tumors, cancer cells coexist and communicate with macrophages that can promote tumorigenesis via pro-inflammatory signals. Lipid mediators (LMs), produced mainly by cyclooxygenases (COXs) or lipoxygenases (LOs), display a variety of biological functions with advantageous or deleterious consequences for tumors. Here, we investigated how the communication between human monocyte-derived M2-like macrophages (MDM) and cancer cells affects LM biosynthesis using LM metabololipidomics. Coculture of human MDM with human A549 epithelial lung carcinoma cells, separated by a semipermeable membrane, increased LM formation by MDM upon subsequent activation. Strongest effects were observed on 5-LO-derived LM. While expression of the 5-LO pathway was not altered, p38 MAPK and the downstream MAPKAPK-2 that phosphorylates and stimulates 5-LO were more susceptible for activation in MDM upon precedent coculture with A549 cells as compared to monocultures. Accordingly, the p38 MAPK inhibitor Skepinone-L selectively prevented this increase in 5-LO product formation. Also, 5-LO-/15-LO-derived LM including lipoxin A4, resolvin D2 and D5 were elevated after coculture with A549 cells, correlating to increased 15-LO-1 protein levels. In contrast to cancer cells, coincubation with non-transformed human umbilical vein endothelial cells (HUVEC) did not affect LM production in MDM. Vice versa, MDM increased COX-2 protein expression and COX-mediated prostanoid formation in cancer cells. Conclusively, our data reveal that the communication between MDM and cancer cells can strikingly modulate the biosynthetic capacities to produce bioactive LM with potential relevance for tumor biology. Keywords Cyclooxygenase · Lipoxygenase · Leukotrienes · Prostaglandins · Specialized pro-resolving mediators Abbreviations AA Arachidonic acid COX Cyclooxygenase cPLA2-α Cytosolic phospholipase A2-α Markus Werner and Simona Pace contributed equally. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00018-019-03413-w) contains supplementary material, which is available to authorized users. * Simona Pace simona.pace@uni‑jena.de * Oliver Werz oliver.werz@uni‑jena.de 1
Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University, Philosophenweg 14, 07743 Jena, Germany
Michael Popp Research Institute, University of Innsbruck, Mitterweg 24, 6020 Innsbruck, Germany
2
DHA Docosahexaenoic acid EPA Eicosapentaenoic acid ERK-1/2 Extracellular signal-regulated protein kinase-1/2 FCS Fetal calf serum FLAP 5-Lipoxygenase-activating protein HETE Hydroxyeicosatet
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