<i>PTEN</i> deletion in luminal cells of mature prostate induces replication stress and senescence in vivo

Abstract

Genetic ablation of the tumor suppressor <i>PTEN</i> in prostatic epithelial cells (PECs) induces cell senescence. However, unlike oncogene-induced senescence, no hyperproliferation phase and no signs of DNA damage response (DDR) were observed in <i>PTEN</i>-deficient PECs; <i>PTEN</i> loss-induced senescence (PICS) was reported to be a novel type of cellular senescence. Our study reveals that <i>PTEN</i> ablation in prostatic luminal epithelial cells of adult mice stimulates PEC proliferation, followed by a progressive growth arrest with characteristics of cell senescence. Importantly, we also show that proliferating <i>PTEN</i>-deficient PECs undergo replication stress and mount a DDR leading to p53 stabilization, which is however delayed by Mdm2-mediated p53 down-regulation. Thus, even though <i>PTEN</i>-deficiency induces cellular senescence that restrains tumor progression, as it involves replication stress, strategies promoting <i>PTEN</i> loss-induced senescence are at risk for cancer prevention and therapy.