A Role for Cellular Senescence in Accelerated Prostate Cell Proliferation: Implication for Benign Prostatic Hyperplasia (BPH)

Presentation Number: THR-134
Date of Presentation: March 5th, 2015

Shoulei Jiang*1, Chung Seog Song1 and Bandana Chatterjee2
1Univ of Texas Hlth Science Ctr, San Antonio, TX, 2Univ of Texas Hlth Science Ctr & South Texas Veterans Health Care System, San Antonio, TX

Abstract

Benign Prostatic Hyperplasia (BPH) is an age-associated progressive disease, afflicting ~90% of men at the ninth decade of life. BPH presents as new glandular or stromal growth of human prostate at the transition zone, which usually is not the site where adenocarcinoma develops.  Pro-inflammatory factors secreted from senescent cells that emerge in prostate during aging are thought to chronically stimulate androgen-induced prostate cell proliferation that leads to enhanced prostate growth, enlargement of the prostate tissue and culminates in BPH(1).  We have developed a novel in vitro model to assess the impact of cellular senescence on the proliferation of epithelial and stromal cells and to identify the mediators, which are drivers of benign prostate growth during physiological aging. Cellular senescence was induced by γ-irradiation (10Gy) of BPH-1 (immortalized epithelial cells from human BPH tissue) and HPS-19I (stromal cells from human prostate; a generous gift from David Rowley, Houston), and the irradiated cells were confirmed to exhibit biomarkers for senescence such as i) senescence-associated lysosomal β-galactosidase (SA-β-gal) activity; ii) elevated expression of p16INK4a, a cell cycle inhibitor and tumor suppressor; and iii) increased levels of hypophosphorylated retinoblastoma protein (pRb).  Judging from biomarker levels, induction of senescence peaked at 9 days post-irradiation. BPH-1 cells proliferated more rapidly upon exposure to the conditioned media from irradiated BPH-1 cells (p = 0.024). BPH-1 proliferation also accelerated upon exposure to the conditioned media from γ-irradiated HPS-19I stromal cells. Pro-inflammatory cytokines IL-1β, IL-6, TNF-α and the CXC-type chemokine CXCL-12 were induced in irradiated cells, revealed from quantitative RT-PCR assay. CXCL-12, one of the major secreted chemokines from senescent cells, markedly enhanced BPH-1 proliferation when added (as a recombinant protein, 1nM) to the culture media for 72 hours (p=0.00095). N-cadherin and Snail, the markers for epithelial-messenchymal transition (EMT), were induced in irradiated cells, suggesting that EMT may partly account for enhanced cell proliferation. Understanding the molecular basis for the interplay of androgen-induced androgen receptor (AR) signaling with senescence-induced EMT and inflammatory signal, and impact of this interplay on prostate growth in vivo can potentially reveal novel avenues for therapeutic intervention of BPH.

 

Nothing to Disclose: SJ, CSS, BC