Abstract
Hyperproliferation of prostate transition-zone epithelial and stromal cells leads to benign prostate hyperplasia (BPH), a prevalent pathology in elderly men. Senescent cells in BPH tissue induce a senescence-associated secretory phenotype (SASP) which, by generating inflamed microenvironment and reactive stroma, promotes leukocyte infiltration, cellular hyperproliferation, and nodular prostate growth. We examined human prostate epithelial (BPH-1, PNT-1α) and stromal (HPS-19I) cells for SASP induction by ionizing radiation and assessed SASP's impacts on cell proliferation and on signal transducers that promote cellular growth, proliferation, and survival. Radiation-induced DNA damage led to cellular senescence, evident from elevated expression of senescence-associated β-galactosidase and the cell-cycle inhibitor p16/INK4a. Clinical BPH tissue showed p16 accumulation. SASP induced mRNA expression for inflammatory cytokines (IL-1α, IL-6, IL-8, TNF-α); chemokines (GM-CSF, CXCL12); metalloproteases (MMP-1, MMP-3, MMP-10); growth factor binding IGFBP-3. Media from irradiated epithelial or stromal cells enhanced BPH-1 proliferation. ERK1/2 and AKT, which enhance cell growth/survival and STAT5, which facilitates cell cycle progression and leukocyte recruitment to epithelial microenvironment, were activated by SASP components. The radiation-induced cellular senescence model can be a platform for identification of individual SASP components and pathways that drive BPH etiology/progression in vivo and targeting them may form the basis for novel BPH therapy.
Original language | English (US) |
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Pages (from-to) | 353-363 |
Number of pages | 11 |
Journal | FASEB BioAdvances |
Volume | 1 |
Issue number | 6 |
DOIs | |
State | Published - Jun 2019 |
Keywords
- AKT
- BPH
- ERK1/2
- SASP
- STAT5
- inflammation
ASJC Scopus subject areas
- Physiology
- Molecular Medicine
- Biochemistry, Genetics and Molecular Biology (miscellaneous)
- Cancer Research