Androgen Receptor Drives Cellular Senescence

Mirochnik, Yelena; Veliceasa, Dorina; Williams, LaTanya V; Maxwell, Kelly M.; Yemelyanov, Alexander; Budunova, Irina; Volpert, Olga V.

doi:10.1371/journal.pone.0031052

Cited by 50 publications

(60 citation statements)

References 66 publications

(87 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The induction of cellular senescence has been described for PC3 cells, a human metastatic PCa cell line that have originally lost AR expression, stably transfected with the human AR and treated with the androgen R1881, defined there as DHT [47]. We confirmed also the androgen-induced cellular senescence in PC3-AR cells.…”

Section: Discussionsupporting

confidence: 78%

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

et al. 2014

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 78%

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

et al. 2014

View full text Add to dashboard Cite

show abstract

“…5A) support that several key changes such as elevated Mcl-1 expression appear to be senescence- rather than AR-dependent. Indeed, AR expression has a complex relationship with senescence induction in prostate cancer cells, with a recent report showing that constitutive AR overexpression can also induce senescence, albeit via a p21-dependent rather than p16-dependent mechanism [86].…”

Section: Discussionmentioning

confidence: 99%

Androgen Deprivation-Induced Senescence Promotes Outgrowth of Androgen-Refractory Prostate Cancer Cells

et al. 2013

View full text Add to dashboard Cite

Androgen deprivation (AD) is an effective method for initially suppressing prostate cancer (PC) progression. However, androgen-refractory PC cells inevitably emerge from the androgen-responsive tumor, leading to incurable disease. Recent studies have shown AD induces cellular senescence, a phenomenon that is cell-autonomously tumor-suppressive but which confers tumor-promoting adaptations that can facilitate the advent of senescence-resistant malignant cell populations. Because androgen-refractory PC cells emerge clonally from the originally androgen-responsive tumor, we sought to investigate whether AD-induced senescence (ADIS) affects acquisition of androgen-refractory behavior in androgen-responsive LNCaP and LAPC4 prostate cancer cells. We find that repeated exposure of these androgen-responsive cells to senescence-inducing stimuli via cyclic AD leads to the rapid emergence of ADIS-resistant, androgen-refractory cells from the bulk senescent cell population. Our results show that the ADIS phenotype is associated with tumor-promoting traits, notably chemoresistance and enhanced pro-survival mechanisms such as inhibition of p53-mediated cell death, which encourage persistence of the senescent cells. We further find that pharmacologic enforcement of p53/Bax activation via Nutlin-3 prior to establishment of ADIS is required to overcome the associated pro-survival response and preferentially trigger pervasive cell death instead of senescence during AD. Thus our study demonstrates that ADIS promotes outgrowth of androgen-refractory PC cells and is consequently a suboptimal tumor-suppressor response to AD.

show abstract

“…A recent application of the same Rbpj-knockout mouse as utilised by Buono et al (2006) has suggested that the basal MECs expansion observed during pregnancy in these mice was due to MECs deficient in NOTCH signalling being outcompeted by WT MECs, supporting the idea that NOTCH signalling is critical for basal bipotent progenitor MECs to take on a luminal fate through suppression of P63 (Yalcin-Ozuysal et al 2010). A role for AR in antagnoising the effects of P63, via the cell cylcle regulator P21, has been identified in prostate epithelium (Mirochnik et al 2012), and it possible that a similar mechanism is at play in the mammary epithelium.…”

Section: Inducible Expression Of Notch1 In All Mecsmentioning

confidence: 92%

Bringing androgens up a NOTCH in breast cancer

Tarulli

Butler

Tilley

et al. 2014

Endocrine-Related Cancer

View full text Add to dashboard Cite

While it has been known for decades that androgen hormones influence normal breast development and breast carcinogenesis, the underlying mechanisms have only been recently elucidated. To date, most studies have focused on androgen action in breast cancer cell lines, yet these studies represent artificial systems that often do not faithfully replicate/ recapitulate the cellular, molecular and hormonal environments of breast tumours in vivo. It is critical to have a better understanding of how androgens act in the normal mammary gland as well as in in vivo systems that maintain a relevant tumour microenvironment to gain insights into the role of androgens in the modulation of breast cancer development. This in turn will facilitate application of androgen-modulation therapy in breast cancer. This is particularly relevant as current clinical trials focus on inhibiting androgen action as breast cancer therapy but, depending on the steroid receptor profile of the tumour, certain individuals may be better served by selectively stimulating androgen action. Androgen receptor (AR) protein is primarily expressed by the hormone-sensing compartment of normal breast epithelium, commonly referred to as oestrogen receptor alpha (ERa (ESR1))-positive breast epithelial cells, which also express progesterone receptors (PRs) and prolactin receptors and exert powerful developmental influences on adjacent breast epithelial cells. Recent lineage-tracing studies, particularly those focussed on NOTCH signalling, and genetic analysis of cancer risk in the normal breast highlight how signalling via the hormone-sensing compartment can influence normal breast development and breast cancer susceptibility. This provides an impetus to focus on the relationship between androgens, AR and NOTCH signalling and the crosstalk between ERa and PR signalling in the hormone-sensing component of breast epithelium in order to unravel the mechanisms behind the ability of androgens to modulate breast cancer initiation and growth.

show abstract

Androgen Receptor Drives Cellular Senescence

Cited by 50 publications

References 66 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

Androgen Deprivation-Induced Senescence Promotes Outgrowth of Androgen-Refractory Prostate Cancer Cells

Bringing androgens up a NOTCH in breast cancer

Contact Info

Product

Resources

About