Abstract
Benign prostate hyperplasia (BPH), an enlargement of the prostate common in aging in men, is associated with urinary voiding dysfunction manifest as Lower Urinary Tract Symptoms (LUTS). Although inflammation and abnormal smooth muscle contractions are known to play key roles in the development of LUTS, tissue fibrosis may also be an important and previously unrecognized contributing factor. Tissue fibrosis arises from the unregulated differentiation of fibroblasts or other precursor cell types into myofibroblasts, which is usually accomplished by activation of the TGFβ/TGFβR axis. Previously we reported that the CXC-type chemokines, CXCL5, CXCL8 and CXCL12, which are up-regulated in the aging in the prostate, can drive this differentiation process as well in the absence of TGFβ. Based on this data we sought to elucidate the molecular mechanisms employed by CXCL12, and its receptor CXCR4, during prostate myofibroblast phenoconversion. The results of these studies suggest that CXCL12/CXCR4-mediated signaling events in prostate myofibroblast phenoconversion may proceed through non-canonical pathways that do not depend on TGFβ/TGFβR axis activation or Smad signaling. Here we report that CXCL12/CXCR4 axis activation promotes signaling through the EGFR and downstream MEK/ERK and PI3K/Akt pathways during myofibroblast phenoconversion, but not through TGFβ/TGFβR and downstream Smad signaling, in prostate fibroblasts undergoing myofibroblast phenoconversion. We document that EGFR transactivation is required for CXCL12-mediated signaling and expression of genes associate with myofibroblast phenoconversion (α-SMA, COL1a1). Our study successfully identified TGFβ/TGFβR-independent molecular mechanisms that promote CXCL12/CXCR4-induced myofibroblast phenoconversion. This information may be crucial for the development of novel therapies and potential biomarkers for prostatic fibrosis.
Highlights
Benign prostate hyperplasia (BPH) is an aging related prostatic enlargement that affects the majority of older men[1]
The same trend was observed in SFT fibroblasts (Fig 1D), EGFR activation was stronger than Erk after CXCl12 treatment
These data indicate that the CXCL12/CXCR4 axis promotes signaling through Smad-independent, non-canonical EGFR and downstream MAPK/Erk and PI3K/Akt pathways in the absence of TGFβ in both N1 and primary prostate fibroblasts
Summary
Benign prostate hyperplasia (BPH) is an aging related prostatic enlargement that affects the majority of older men[1]. The results of these studies showed that activation of the CXCL12/CXCR4 axis rapidly but phosphorylated the EGFR at tyrosine 1068 as well as downstream MAPK/Erk and PI3K/Akt signaling pathways, but did not promote Smad3 phosphorylation, in both N1 (Fig 1A) and SFT1 (Fig 1B) cells.
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