Abstract
BackgroundProstate cancer (PCa) is the second leading cause of cancer mortality of men in Western countries. The androgen receptor (AR) and AR-agonists (androgens) are required for the development and progression of the normal prostate as well as PCa. However, it is discussed that in addition to their tumor promoting activity, androgens may also exhibit tumor suppressive effects. A biphasic growth response to androgens a growth-promoting and -inhibition has been observed that suggests that administration of supraphysiological androgen levels mediates growth reduction in AR expressing PCa cells.MethodsDetection of senescence markers, three dimensional interphase fluorescence in situ hybridization (3D-iFISH), qRT-PCR, Western blotting, detection of GFP fusions, prostatectomy, ex vivo culturing.ResultsHere, we describe that supraphysiological levels of androgens induce cell cycle arrest and markers of cellular senescence in human PCa cells, which may in part explain the growth inhibitory role of androgens. The expression of the senescence associated beta galactosidase is observed by treatment with the natural androgen DHT or the less metabolized synthetic androgen R1881. The induction of senescence marker was detected in human PCa cell lines as well as in human primary PCa tissue derived from prostatectomy treated ex vivo. Using interphase FISH (iFISH) suggests that the androgen-induced cellular senescence is associated with localizing the genomic E2F1 locus to senescence associated heterochromatic foci. Analysis of different signaling pathways in LNCaP cells suggest that the p16-Rb-E2F1 pathway is essential for the induction of cellular senescence since treatment with siRNA directed against p16 reduces the level of androgen-induced cellular senescence. Based on the rapid induction of androgen-mediated cellular senescence we identified the Src-PI3K-Akt-signaling pathway and autophagy being in part involved in androgen regulation.ConclusionsTaken together, our data suggest that AR-agonists at supraphysiological levels mediate induction of cellular senescence in human PCa cells, which may have a protective anti-cancer role. These results provide also new insights for understanding androgen-mediated regulation of PCa growth.Electronic supplementary materialThe online version of this article (doi:10.1186/1476-4598-13-214) contains supplementary material, which is available to authorized users.
Highlights
Prostate cancer (PCa) is the second leading cause of cancer mortality of men in Western countries
Androgen-dependent growing LNCaP cells were treated with DHT and R1881 for 3 days and through the measurement of SA Senescence-associated beta-galactosidase (β-Gal) activity the induction of cellular senescence was analyzed
Administration of 1 nM R1881 or 1 nM DHT indicate a strong induction of SA β-Gal activity, in contrast, lower androgen levels show the basal level of cellular senescence similar to the untreated or the solvent control (Figure 1A, B)
Summary
Prostate cancer (PCa) is the second leading cause of cancer mortality of men in Western countries. Prostate Cancer (PCa) is an important age-related diseases being the most common cancer malignancy and the second leading cause of cancer mortality in men in western countries [1]. Cellular senescence is an irreversible cell cycle arrest mediated through exogenous and endogenous stimuli, which cause changes in cell morphology and gene expression profiles [10,11]. This program of cell cycle arrest by cellular senescence seems to be inhibited [14]. The process of cellular senescence represents a natural defense mechanism against tumor progression and the exogenous re-activation and induction of cellular senescence is a potential target for cancer therapy [15]
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