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-κB signaling in PCa cells and that this increase is associated with FGFR1 expression. Disruption of FGFR1 kinase activity abrogated both FGF activity and NF-κB 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-κB signaling. Instead, transforming growth factor β-activating kinase 1 (TAK1), a central regulator of the NF-κB pathway, was required for FGFR1 to stimulate NF-κB signaling. Moreover, we found that FGFR1 promotes NF-κB signaling in PCa cells by reducing TAK1 degradation and thereby supporting sustained NF-κB 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.

The molecular mechanism by which interleukin 6 (IL-6) induces terminal differentiation of B cells was investigated in a subpopulation of the clonal human Blymphoblastoid cell line CESS selected for high density of cell surface IgGi. Induction of CESS cells with IL-6 resulted in a 15-fold preferential accumulation of secreted-specific yV (YVs) mRNA but not of the alternatively processed membranespecific Vi (ylm) mRNA. Similarly, p, mRNA but not the Sum mRNA of the nonproductively rearranged I% heavy-chain allele was also increased. Accompanying the differential accumulation of yVs mRNA was a 4.5-fold increase in A light-chain mRNA, leading to secretion of IgGi. Analyses of transcription in isolated nuclei demonstrated that transcriptional activation was the primary mechanism for quantitative increase of immunoglobulin mRNAs (5.5-fold for yV and jA and at least 2-fold for A). Since polymerase loading is diminished by 75% before reaching the downstream ylm polyadenylylation site in CESS cells, irrespective of IL-6 induction, transcriptional pausing/ termination appears intrinsic and contributes to the selection of Vys and ylm polyadenylylation sites in activated B cells.

Advanced castrate-resistant prostate cancer (CRPC) is a poorly prognostic disease currently lacking effective cure. Understanding the molecular mechanism that underlies the initiation and progression of CRPC will provide new strategies for treating this deadly disease. One candidate target is the fibroblast growth factor (FGF) signaling axis. Loss of the intrinsic FGF7/FGF10-type 2 FGF receptor (FGFR2) pathway and gain of the ectopic type 1 FGF receptor (FGFR1) pathway are associated with the progression to malignancy in prostate cancer (PCa) and many other epithelial originating lesions. Although FGFR1 and FGFR2 share similar amino acid sequences and structural domains, the two transmembrane tyrosine kinases elicit distinctive, even sometime opposite signals in cells. Recent studies have revealed that the ectopic FGFR1 signaling pathway contributes to PCa progression via multiple mechanisms, including promoting tumor angiogenesis, reprogramming cancer cell metabolism, and potentiating inflammation in the tumor microenvironment. Thus, suppression of FGFR1 signaling can be an effective novel strategy to treat CRPC.