Supraphysiological androgen levels induce cellular senescence in human prostate cancer cells through the Src-Akt pathway

Molecular Cancer

Research

Aria Baniahmad¹  Mohsen Esmaeili¹  Soeren S Huettner¹  Sophie Bartsch¹  Wiebke Hessenkemper¹  Marina Manvelyan¹  Thomas Liehr¹  Julia Roediger²  Iver Petersen³  Marc-Oliver Grimm⁴  Susan Foller⁴ 

[1] Institute of Human Genetics, Jena University Hospital, 07740, Jena, Germany;Institute of Human Genetics, Jena University Hospital, 07740, Jena, Germany;National Institutes of Health (NIH), Section on Molecular Morphogenesis, 20892-5431, Bethesda, MD, USA;Institute of Pathology, Jena University Hospital, 07740, Jena, Germany;Institute of Urology, Jena University Hospital, 07740, Jena, Germany;

关键词: Nuclear receptor;    Non-genomic signaling;    Tumor suppression;    Cellular senescence;    Autophagy;   

DOI  :  10.1186/1476-4598-13-214

 received in 2014-04-24, accepted in 2014-08-27,  发布年份 2014

来源: Springer

【 摘 要 】

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.

【 授权许可】

Unknown   
© Roediger et al.; licensee BioMed Central Ltd. 2014. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.