1445 ANDROGEN DEPRIVATION INDUCES A DELAYED SENESCENT PHENOTYPE IN PROSTATE CANCER

You have accessJournal of UrologyProstate Cancer: Basic Research1 Apr 20111445 ANDROGEN DEPRIVATION INDUCES A DELAYED SENESCENT PHENOTYPE IN PROSTATE CANCER Jonathan Ewald, Joshua Desotelle, Dawn Church, Timo Laurila, and David Jarrard Jonathan EwaldJonathan Ewald Madison, WI More articles by this author , Joshua DesotelleJoshua Desotelle Madison, WI More articles by this author , Dawn ChurchDawn Church Madison, WI More articles by this author , Timo LaurilaTimo Laurila Madison, WI More articles by this author , and David JarrardDavid Jarrard Madison, WI More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2011.02.1358AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Prostate cancers regress after androgen deprivation (AD) therapy, but the fate of persistent cells is largely undefined. Apoptosis (3–7%) and cellular necrosis occurs in a subset of cells. Cellular senescence is a cytostatic response to a sub-lethal stress under which cells become terminally growth arrested and develop distinct morphological and biochemical characteristics. We hypothesized that AD may induce a senescence phenotype in prostate cancer cells. METHODS Time course experiments over 9 days using the androgen-sensitive LNCaP prostate cancer cell lines were performed in media containing either complete fetal bovine serum or androgen-deficient charcoal-stripped serum. LuCap 58 and 23 human xenografts were then examined under both castrate and intact conditions. Cell sorting parameters and other protein markers of senescence, including senescence-associated â-galactosidase (SA-â-gal) activity, p27, SKP2, and Glb1, were utilized. Apoptosis was assessed using Annexin V/propidium iodide and caspase 3 staining. RESULTS AD significantly decreases the proliferation of cells as determined by cell counting, decreased S-phase, and reduced KI67. AD decreased cell viability minimally(8-10%), and induced apoptosis rapidly in a subset of cells(5-7%) over this time period. Characteristics of senescence, including increased flow cytometric side scatter (SSC), and SA-â-gal activity rapidly peaked and remained elevated at 6 days after AD. Immunoblot analysis demonstrated increased expression of the senescence-related Glb1 protein and the cyclin-dependent kinase inhibitor protein p27Kip1. We then assessed LuCaP xenograft tumors up to 10 days after surgical castration or sham surgery. Immunohistochemical analysis of tumors from castrated mice showed significant increases in apoptosis as assessed by cleaved caspase 3(8%) and decreased ki67(30%). Xenografts at 3 and 10 days demonstrated increased p27Kip1 and SA-â-gal staining (p<0.05). Western blot of pooled tumor lysates confirmed the increased expression of p27Kip1 and Glb1. CONCLUSIONS We conclude that AD induces characteristics of cellular senescence in a subset of androgen-sensitive prostate cancer cells both in vitro and in vivo. Senescence temporally occurs later than apoptosis. The ultimate fate of these cells and the biologic significance of their presence has yet to be defined, but may have implications with regard to recurrence after therapy. © 2011 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 185Issue 4SApril 2011Page: e579-e580 Advertisement Copyright & Permissions© 2011 by American Urological Association Education and Research, Inc.Metrics Author Information Jonathan Ewald Madison, WI More articles by this author Joshua Desotelle Madison, WI More articles by this author Dawn Church Madison, WI More articles by this author Timo Laurila Madison, WI More articles by this author David Jarrard Madison, WI More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...