Resolvin D1 inhibits TGF-β1-induced epithelial mesenchymal transition of A549 lung cancer cells via lipoxin A4 receptor/formyl peptide receptor 2 and GPR32

Int J Biochem Cell Biol. 2013 Dec;45(12):2801-7. doi: 10.1016/j.biocel.2013.09.018. Epub 2013 Oct 10.


Epithelial-mesenchymal-transition (EMT) is a key event for tumor cells to initiate metastasis which lead to switching of E-cadherin to N-cadherin. Resolvins are known to promote the resolution of inflammation and phagocytosis of macrophages. However, the role of resolvins in EMT of cancer is not known. Therefore, we examined the effects of resolvins on transforming growth factor, beta 1 (TGF-β1)-induced EMT. Expression of E-cadherin and N-cadherin in A549 lung cancer cells was evaluated by Western blot and confocal microscopy. Involvement of lipoxin A4 receptor/formyl peptide receptor 2 (ALX/FPR2) was examined by gene silencing. TGF-β1 induced expression of N-cadherin in A549 lung cancer cells, and resolvin D1 and D2 inhibited the expression of N-cadherin at low concentrations (1-100 nM). Resolvin D1 and D2 also suppressed the expression of zinc finger E-box binding homeobox 1 (ZEB1). The effects of resolvin D1 and D2 were confirmed in other lung cancer cell lines such as H838, H1299, and H1703. Resolvin D1 and D2 did not affect the proliferation of A549 lung cancer cells. Resolvin D1 and D2 also suppressed the TGF-β1-induced morphological change. Resolvin D1 and D2 also inhibited the TGF-β1-induced migration and invasion of A549 cells. Resolvin D1 is known to act via ALX/FPR2 and GPR32. Thus, we examined the involvement of ALX/FPR2 and GPR32 in the suppressive effects of resolvin D1 on TGF-β1-induced EMT of A549 cells. Gene silencing of ALX/FPR2 and GPR32 blocked the action of resolvin D1. Overexpression of ALX/FPR2 or GPR32 increased the effects of resolvin D1. These results suggest that resolvin D1 inhibited TGF-β1-induced EMT via ALX/FPR2 and GPR32 by reducing the expression of ZEB1.

Keywords: A549 lung cancer cell; Lipoxin A4 receptor/formyl peptide receptor 2; N-cadherin expression; Resolvin; TGF-β1-induced epithelial mesenchymal transition.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Docosahexaenoic Acids / metabolism*
  • Epithelial-Mesenchymal Transition
  • Humans
  • Lipoxins / genetics
  • Lipoxins / metabolism*
  • Lung Neoplasms / genetics
  • Lung Neoplasms / metabolism*
  • Lung Neoplasms / pathology*
  • RNA, Small Interfering / administration & dosage
  • RNA, Small Interfering / genetics
  • Receptors, Formyl Peptide / metabolism*
  • Receptors, G-Protein-Coupled / genetics*
  • Receptors, G-Protein-Coupled / metabolism
  • Transfection
  • Transforming Growth Factor beta1 / antagonists & inhibitors*
  • Transforming Growth Factor beta1 / pharmacology


  • GPR32 protein, human
  • Lipoxins
  • RNA, Small Interfering
  • Receptors, Formyl Peptide
  • Receptors, G-Protein-Coupled
  • Transforming Growth Factor beta1
  • lipoxin A4
  • resolvin D1
  • Docosahexaenoic Acids