Molecular aspects of prostate cancer

Cronauer, Marcus V.; Čulig, Zoran

doi:10.1007/s00345-012-0853-x

Cited by 2 publications

(1 citation statement)

References 11 publications

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“…Initially, PCa progression is androgen receptor (AR)- and androgen-dependent. Unfortunately, after 12–18 months of hormone ablation therapy the advanced PCa growth is becoming androgen-independent but remains dependent on AR [2], which indicates the importance of developing new therapeutic strategies. Interestingly, it is known that with increased age the androgen level is decreasing, which seems to be timely associated with increased risk of PCa [3, 4].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2014

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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.

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Section: Introductionmentioning

confidence: 99%

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

et al. 2014

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Coactivator MYST1 Regulates Nuclear Factor-κB and Androgen Receptor Functions During Proliferation of Prostate Cancer Cells

Jaganathan

Chaurasia

Xiao

et al. 2014

Molecular Endocrinology

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In prostate cancer (PCa), the functional synergy between androgen receptor (AR) and nuclear factor-κ B (NF-κB) escalates the resistance to therapeutic regimens and promotes aggressive tumor growth. Although the underlying mechanisms are less clear, gene regulatory abilities of coactivators can bridge the transcription functions of AR and NF-κB. The present study shows that MYST1 (MOZ, YBF2 and SAS2, and TIP60 protein 1) costimulates AR and NF-κB functions in PCa cells. We demonstrate that activation of NF-κB promotes deacetylation of MYST1 by sirtuin 1. Further, the mutually exclusive interactions of MYST1 with sirtuin 1 vs AR regulate the acetylation of lysine 16 on histone H4. Notably, in AR-lacking PC3 cells and in AR-depleted LNCaP cells, diminution of MYST1 activates the cleavage of poly(ADP-ribose) polymerase and caspase 3 that leads to apoptosis. In contrast, in AR-transformed PC3 cells (PC3-AR), depletion of MYST1 induces cyclin-dependent kinase (CDK) N1A/p21, which results in G2M arrest. Concomitantly, the levels of phospho-retinoblastoma, E2F1, CDK4, and CDK6 are reduced. Finally, the expression of tumor protein D52 (TPD52) was unequivocally affected in PC3, PC3-AR, and LNCaP cells. Taken together, the results of this study reveal that the functional interactions of MYST1 with AR and NF-κB are critical for PCa progression.

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Molecular aspects of prostate cancer

Cited by 2 publications

References 11 publications

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

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

Coactivator MYST1 Regulates Nuclear Factor-κB and Androgen Receptor Functions During Proliferation of Prostate Cancer Cells

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