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Ceramide and palmitic acid inhibit macrophage-mediated epithelial–mesenchymal transition in colorectal cancer

Authors
  • de Araujo Junior, Raimundo Fernandes1, 1, 1, 2
  • Eich, Christina2
  • Jorquera, Carla2
  • Schomann, Timo3, 2
  • Baldazzi, Fabio2
  • Chan, Alan B.3, 2
  • Cruz, Luis J.2
  • 1 Federal University of Rio Grande do Norte, Natal, RN, 59072-970, Brazil , Natal (Brazil)
  • 2 Leiden University Medical Center, Leiden, 2333 ZA, The Netherlands , Leiden (Netherlands)
  • 3 Percuros B.V., Leiden, 2333 CL, The Netherlands , Leiden (Netherlands)
Type
Published Article
Journal
Molecular and Cellular Biochemistry
Publisher
Springer-Verlag
Publication Date
Mar 28, 2020
Volume
468
Issue
1-2
Pages
153–168
Identifiers
DOI: 10.1007/s11010-020-03719-5
Source
Springer Nature
Keywords
License
Green

Abstract

Accumulating evidence indicates that ceramide (Cer) and palmitic acid (PA) possess the ability to modulate switching of macrophage phenotypes and possess anti-tumorigenic effects; however, the underlying molecular mechanisms are largely unknown. The aim of the present study was to investigate whether Cer and PA could induce switching of macrophage polarization from the tumorigenic M2- towards the pro-inflammatory M1-phenotype, and whether this consequently altered the potential of colorectal cancer cells to undergo epithelial–mesenchymal transition (EMT), a hallmark of tumor progression. Our study showed that Cer- and PA-treated macrophages increased expression of the macrophage 1 (M1)-marker CD68 and secretion of IL-12 and attenuated expression of the macrophage 2 (M2)-marker CD163 and IL-10 secretion. Moreover, Cer and PA abolished M2 macrophage-induced EMT and migration of colorectal cancer cells. At the molecular level, this coincided with inhibition of SNAI1 and vimentin expression and upregulation of E-cadherin. Furthermore, Cer and PA attenuated expression levels of IL-10 in colorectal cancer cells co-cultured with M2 macrophages and downregulated STAT3 and NF-κB expression. For the first time, our findings suggest the presence of an IL-10-STAT3-NF-κB signaling axis in colorectal cancer cells co-cultured with M2 macrophages, mimicking the tumor microenvironment. Importantly, PA and Cer were powerful inhibitors of this signaling axis and, consequently, EMT of colorectal cancer cells. These results contribute to our understanding of the immunological mechanisms that underlie the anti-tumorigenic effects of lipids for future combination with drugs in the therapy of colorectal carcinoma.

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