Open AccessArachidonic acid, a clinically adverse mediator in the ovarian cancer microenvironment, impairs JAK‐STAT signaling in macrophages by perturbing lipid raft structures
Author(s) -
Hammoud Mohamad K.,
Dietze Raimund,
Pesek Jelena,
Finkernagel Florian,
Unger Annika,
Bieringer Tim,
Nist Andrea,
Stiewe Thorsten,
Bhagwat Aditya M.,
Nockher Wolfgang Andreas,
Reinartz Silke,
MüllerBrüsselbach Sabine,
Graumann Johannes,
Müller Rolf
Publication year - 2022
Publication title -
molecular oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.332
H-Index - 88
eISSN - 1878-0261
pISSN - 1574-7891
DOI - 10.1002/1878-0261.13221
Subject(s) - lipid raft , tumor microenvironment , biology , phosphorylation , signal transduction , cancer research , microbiology and biotechnology , lipid signaling , arachidonic acid , socs3 , stat1 , stat3 , immune system , receptor , immunology , biochemistry , enzyme
Survival of ovarian carcinoma is associated with the abundance of immunosuppressed CD163 high CD206 high tumor‐associated macrophages (TAMs) and high levels of arachidonic acid (AA) in the tumor microenvironment. Here, we show that both associations are functionally linked. Transcriptional profiling revealed that high CD163 and CD206/MRC1 expression in TAMs is strongly associated with an inhibition of cytokine‐triggered signaling, mirrored by an impaired transcriptional response to interferons and IL‐6 in monocyte‐derived macrophages by AA. This inhibition of pro‐inflammatory signaling is caused by dysfunctions of the cognate receptors, indicated by the inhibition of JAK1, JAK2, STAT1, and STAT3 phosphorylation, and by the displacement of the interferon receptor IFNAR1, STAT1 and other immune‐regulatory proteins from lipid rafts. AA exposure led to a dramatic accumulation of free AA in lipid rafts, which appears to be mechanistically crucial, as the inhibition of its incorporation into phospholipids did not affect the AA‐mediated interference with STAT1 phosphorylation. Inhibition of interferon‐triggered STAT1 phosphorylation by AA was reversed by water‐soluble cholesterol, known to prevent the perturbation of lipid raft structure by AA. These findings suggest that the pharmacologic restoration of lipid raft functions in TAMs may contribute to the development new therapeutic approaches.