Ectopic fibroblast growth factor receptor 1 promotes inflammation by promoting nuclear factor-кB signaling in prostate cancer cells

Cong Wang, Yuepeng Ke, Shaoyou Liu, Sharon Pan, Ziying Liu, Hui Zhang, Zhichao Fan, Changyi Zhou, Junchen Liu, Fen Wang

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

Initiation of expression of fibroblast growth factor receptor 1 (FGFR1) concurrent with loss of FGFR2 expression is a well-documented event in the progression of prostate cancer (PCa). Although it is known that some FGFR isoforms confer advantages in cell proliferation and survival, the mechanism by which the subversion of different FGFR isoforms contributes to PCa progression is incompletely understood. Here, we report that fibroblast growth factor (FGF) promotes NF-кB signaling in PCa cells and that this increase is associated with FGFR1 expression. Disruption of FGFR1 kinase activity abrogated both FGF activity and NF-кB signaling in PCa cells. Of note, the three common signaling pathways downstream of FGFR1 kinase, extracellular signal–regulated kinase 1/2 (ERK1/2), phosphoinositide 3-kinase (PI3K/AKT), and phosphoinositide phospholipase Cγ (PLCγ), were not required for FGF-mediated NF-кB signaling. Instead, transforming growth factor β–activating kinase 1 (TAK1), a central regulator of the NF-кB pathway, was required for FGFR1 to stimulate NF-кB signaling. Moreover, we found that FGFR1 promotes NF-кB signaling in PCa cells by reducing TAK1 degradation and thereby supporting sustained NF-кB activation. Consistently, Fgfr1 ablation in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model reduced inflammation in the tumor microenvironment. In contrast, activation of the FGFR1 kinase in the juxtaposition of chemical-induced dimerization (CID) and kinase 1 (JOCK1) mouse model increased inflammation. As inflammation plays an important role in PCa initiation and progression, these findings suggest that ectopically expressed FGFR1 promotes PCa progression, at least in part, by increasing inflammation in the tumor microenvironment.

Original languageEnglish (US)
Pages (from-to)14839-14849
Number of pages11
JournalJournal of Biological Chemistry
Volume293
Issue number38
DOIs
StatePublished - Sep 21 2018

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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