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.
Highlights
Hyperproliferation of non‐tumorigenic prostate cells, especially prostate epithelial cells, leads to benign prostate hyperplasia (BPH), a progressive disease that affects about ~50% men in their 50s and 60s, and up to 80% men by age 85.1-3 BPH manifests as new glandular epithelial growth and, less frequently, stromal cell growth at the prostate transition zone surrounding the upper portion of the prostatic urethra—a site less susceptible to cancer development
Given our supposition that senescence‐associated secretory phenotype (SASP) of senescent prostate cells contributes to cellular hyperproliferation that culminates in aberrant glandular prostate growth, we examined BPH specimens for the expression of p16/INK4a, which is a biomarker for cellular senescence
We employed DNA damage‐induced premature senescence of gamma‐irradiated human prostate cells as a model to investigate the impacts of SASP on prostate epithelial cell proliferation and on signal transducers that regulate cell growth, proliferation, and survival
Summary
Hyperproliferation of non‐tumorigenic prostate cells, especially prostate epithelial cells, leads to benign prostate hyperplasia (BPH), a progressive disease that affects about ~50% men in their 50s and 60s, and up to 80% men by age 85.1-3 BPH manifests as new glandular epithelial growth and, less frequently, stromal cell growth at the prostate transition zone surrounding the upper portion of the prostatic urethra—a site less susceptible to cancer development. Epithelial and stromal factors that influence the interplay between aging and prostate cell growth may inform new avenues for the optimal intervention of BPH/ LUTS. As a cell‐intrinsic tumor‐suppressive mechanism, cellular senescence bars aberrant proliferation of cells that are irreversibly damaged by insults such as oxidative stress induced by cell's metabolic activities, chromosomal instability from shortened telomeres, and DNA damage by chemicals or ionizing radiation. Cells of the BPH epithelium and late‐passage epithelial cells isolated from the normal prostate transition zone showed elevated p16/ INK4a and SA‐βGal.[6,11,12]. SASP was associated with (a) elevated mRNAs for inflammatory cytokines, chemokines, growth factors, and metalloproteases; (b) activation of the signal transducer STAT5, which promotes cell cycle progression and leukocyte infiltration into tissue microenvironment; and (c) activation of ERK1/2 and AKT, which regulate cell growth and survival. Irradiated prostate cells and resulting premature senescence can be used as an experimental platform to identify SASP components and signal networks that regulate BPH pathogenesis, and their targeting may afford novel intervention of this disease
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