NF-κB-dependent transcriptional activation in lung carcinoma cells by farnesol involves p65/RelA(Ser276) phosphorylation via the MEK-MSK1 signaling pathway

Academic Article


  • In this study, we demonstrate that treatment of human lung adenocarcinoma H460 cells with farnesol induces the expression of a number of immune response and inflammatory genes, including IL-6, CXCL3, IL-1α, and COX-2. This response was dependent on the activation of the NF-κB signaling pathway. Farnesol treatment reduces the level of IκBα and induces translocation of p65/RelA to the nucleus, its phosphorylation at Ser 276, and transactivation of NF-κB-dependent transcription. Moreover, overexpression of IκBα or treatment with the NF-κB inhibitor caffeic acid phenethyl ester greatly diminishes the induction of inflammatory gene expression by farnesol. We provide evidence indicating that the farnesol-induced phosphorylation of p65/RelA at Ser276 is important for optimal transcriptional activity of NF-κB. The MEK1/2 inhibitor U0126 and knockdown of MEK1/2 expression with small interfering RNAs effectively blocked the phosphorylation of p65/RelA(Ser276) but not that of Ser536, suggesting that this phosphorylation is dependent on the activation of the MEK1/2-ERK1/2 pathway. We further show that inhibition of MSK1, a kinase acting downstream of MEK1/2-ERK1/2, by H89 or knockdown of MSK1 expression also inhibited phosphorylation of p65/RelA(Ser276), suggesting that this phosphorylation is dependent on MSK1. Knockdown of MEK1/2 or MSK1 expression inhibits farnesol-induced expression of CXCL3, IL-1α, and COX-2 mRNA. Our results indicate that the induction of inflammatory genes by farnesol is mediated by the activation of the NF-κB pathway and involves MEK1/2-ERK1/2-MSK1-dependent phosphorylation of p65/RelA (Ser276). The activation of the NF-κB pathway by farnesol might be part of a prosurvival response during farnesol-induced ER stress.
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    Digital Object Identifier (doi)

    Author List

  • Joung HJ; Jetten AM
  • Start Page

  • 16391
  • End Page

  • 16399
  • Volume

  • 283
  • Issue

  • 24