Androgen deprivation induces senescence characteristics in prostate cancer cells in vitro and in vivo.
BACKGROUND
The treatment of non-localized prostate cancer involves androgen deprivation (AD) therapy which results in tumor regression. Apoptosis has been implicated in the tumor response to AD, but constitutes a small fraction of the total tumor at any time. Cellular senescence is a response to sub-lethal stress in which cells are persistently growth arrested and develop distinct morphological and biochemical characteristics. The occurrence of senescence in prostate tumor tissue after AD therapy has not previously been investigated.


METHODS
Phenotypic and molecular characteristics of senescence were examined in models of androgen-sensitive prostate cancer after AD and compared with androgen-intact controls.


RESULTS
In vitro in LNCaP cells, AD induced elevated senescence-associated β-galactosidase (SA-β-gal) staining, decreased proliferation, and increased flow cytometric side scatter while minimally affecting cell viability. The increased expression of the senescence-related proteins Glb1, the cyclin-dependent kinase inhibitor p27(Kip1) and chromatin-regulating heterochromatin protein 1γ (HP1γ) were detected in LNCaP cells after AD in vitro by immunoblot and immunofluorescence microscopy. In mice bearing LuCaP xenograft tumors in vivo, surgical castration similarly increased SA-β-gal staining, increased expression of p27(Kip1) and HP1γ, and decreased expression of the proliferation marker KI-67, with minimal induction of apoptosis identified by detection of cleaved caspase 3 and TUNEL. Immunohistochemical analysis of human prostate tumors removed after AD shows similar induction of Glb1, HP1γ and decreased KI-67.


CONCLUSIONS
We conclude that AD induces characteristics consistent with cellular senescence in androgen-sensitive prostate cancer cells. This finding may explain incomplete tumor regression in response to AD.
Department of Urology, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin 53705-2275, USA.
Jonathan A
JA
Ewald
Joshua A
JA
Desotelle
Dawn R
DR
Church
Bing
B
Yang
Wei
W
Huang
Timo A
TA
Laurila
David F
DF
Jarrard
D000368:Aged; D000728:Androgens / Q000172:deficiency* / Q000494:pharmacology; D000818:Animals; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D023041:Xenograft Model Antitumor Assays / Q000379:methods
D000728:Androgens