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Communication between human macrophages and epithelial cancer cell lines dictates lipid mediator biosynthesis

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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.

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Abbreviations

AA:

Arachidonic acid

COX:

Cyclooxygenase

cPLA2-α:

Cytosolic phospholipase A2-α

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:

Hydroxyeicosatetraenoic acid

HUVEC:

Human umbilical vein endothelial cells

LM:

Lipid mediator

LO:

Lipoxygenase

LT:

Leukotriene

MAPK:

Mitogen-activated protein kinase

MK-2:

MAPKAPK-2, mitogen-activated protein kinase-activated protein kinase-2

MDM:

Monocyte-derived macrophages

NSAID:

Non-steroidal anti-inflammatory drugs

PG:

Prostaglandin

SPM:

Specialized pro-resolving mediators

TAM:

Tumor-associated macrophages

TME:

Tumor microenvironment

UPLC-MS–MS:

Ultra performance liquid chromatography-tandem mass spectrometry

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Acknowledgements

This work was supported by the Deutsche Forschungsgemeinschaft (SFB1127 ChemBioSys and SFB1278 Polytarget). J.G. received a Carl Zeiss stipend.

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Author notes

  1. Markus Werner and Simona Pace contributed equally.

Authors and Affiliations

  1. Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University, Philosophenweg 14, 07743, Jena, Germany

    Markus Werner, Simona Pace, Anna Czapka, Paul M. Jordan, Jana Gerstmeier, Andreas Koeberle & Oliver Werz

  2. Michael Popp Research Institute, University of Innsbruck, Mitterweg 24, 6020, Innsbruck, Germany

    Andreas Koeberle

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  1. Markus Werner
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Werner, M., Pace, S., Czapka, A. et al. Communication between human macrophages and epithelial cancer cell lines dictates lipid mediator biosynthesis. Cell. Mol. Life Sci. 77, 4365–4378 (2020). https://doi.org/10.1007/s00018-019-03413-w

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